anesthesiologie Nederlands tijdschrift voor Wetenschap special volume 21, augustus 20094

Nederlands tijdschrift voor

anesthesiologie Wetenschap special

volume 21, augustus 2009

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• Wetenschappelijk onderzoek – investeren in talenten S.A. Loer

• Abstracts Wetenschapsdag 2009

Dr. M. Klimek, hoofdredacteur Prof. Dr. M.A.E. Marcus, plaatsvervangend hoofdredacteur

Officiële uitgave van de Nederlandse Vereniging voor Anesthesiologie

Eldering_NTvA 04 v5.indd 1

• Scientiﬁc Misconduct in Anesthesia Research: No Exception to the Rule J.W. van Kleef, J. Loadsman, S. Shafer, A. Dahan • Opioïd-geïnduceerde hyperalgesie ontstaat onafhankelijk van opioïdreceptor-activatie E.Y. Sarton

09-09-09 11:52

“Op mijn leeftijd slik je niet zomaar iets tegen de pijn”

Wil van Brakel, 62 jaar heeft last van lage rugpijn.

Zaldiar. De paracetamol plus alle voordelen van paracetamol plus de kracht van tramadol minimaal risico op orgaanschade bekend, vertrouwd en volledig vergoed 1,2,3

4,5,6,7

60 plus. Zaldiar dus. paracetamol 325 mg + tramadol 37,5 mg


09-09-09 11:52

Ernstige, onverwachte bloeding subcutaan, weke delen

Tijdig denken aan verworven hemofilie kan een leven redden

022567_N7adv_210x277_fc.indd 1 Eldering_NTvA 04 v5.indd 1

02-10-2008 10:51:29 09-09-09 11:01

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nederlands tijdschrift voor anesthesiologie augustus '09

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inhoud Nederlands tijdschrift voor

anesthesiologie Coverbeeld: Shutterstock

volume 21 Nummer 4 augustus 2009

editorial

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Wetenschappelijk onderzoek – investeren in talenten S.A. Loer

abstracts wetenschapsdag 2009 o r a l p r e s e n tat i on

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Effects of high altitude hypoxia and iloprost on right ventricular function in healthy volunteers

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The selective a7nAChR agonist GTS-21 attenuates ventilator-induced inflammation and lung injury

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Left ventricular ejection fraction assessed by 2D and 3D echocardiography: Does experience matter?

o r a l p r e s e n tat i on

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Cerebral autoregulation is unaltered by sympathetic denervation with stellate ganglionic blockade

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M. Swartjes, A. Dahan, A.M. Morariu 10

Molecular diagnosis of ryr1 gene mutations causative for susceptibility to malignant hyperthermia and/or central core disease using the MLPA method


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J.M.K. van Fessem, A.A. van Maris, R.A.J.M. Willems, P.G.J. ten Koppel, A.J.W. Teunissen, R.J. Stolker

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Acute pain stress increases phosphorylation of DCLK-long in the rat Edinger-Westphal nucleus but not in the hypothalamic paraventricular nucleus

Does a field block reduce the incidence of postoperative pain, nausea and vomiting in oncologic breast surgery? P.M.L.E. Riezebos, M.M.J. Snoeck, L.J.A. Strobbe

poster walk around groep 1

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Fentanyl induces hyperalgesia in humans and mice E.Y. Sarton, A. Dahan, J. Grefkens, B. Kest, M. Boom, E. van Dorp 17

E.A.C. Bouman, H.M.S. Theunissen, A.G. Kessels, M.A.E. Marcus, H.F. Gramke poster walk around groep 1

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Predicting the time course of sensory block after intrathecal injection of lidocaine M.A. Holtkamp, D.J. Eleveld, A.M. van Oort, S. Schiere poster walk around groep 1

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Chronic neuropathic pain: structural changes in the superficial dorsal spinal cord

T.P.H. Rouwette, L.T. Kozicz, N.F.M. Olde Loohuis, B. Gaszner, E. Vreugdenhil, G.J. Scheffer, E.W. Roubos, K.C. Vissers, W.J.J.M. Scheenen poster walk around groep 1

M.S. Snoeck, J.C.F. Koenen, Y. Aardsen, C. Klaasen

M.J. Sigtermans, J. van Cosburgh, A. Dahan


F.H. Tijssen, V.M. Smit-Fun, V.C.M.L Timmer, A. Kroese, M.A.E. Marcus, M.D. Lance


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S(+)-ketamine effect on chronic pain and experimental acute pain in Complex Regional Pain Syndrome type 1 patients

Paravertebral block for analgesia after major oncologic breast surgery: a comparison of continuous paravertebral block, single shot paravertebral block, and single shot wound infiltration

Midazolam premedication for children undergoing T&A?

Effect of N-methyl-D-aspartate receptor (NMDA-R) antagonists in a rat model of neuropathic pain

F.M. Wulfert, M. van Meurs, N.F. Kurniati, R. M. Jongman, J.G. Zijlstra, M. M. R. Struys, G. Molema

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Impact of platelet function analysis on decision making in preeclampsia


R.H.A. Passier, R.V. Immink, J. Truijen, J.H. Vranken, M.H. van der Vegt, M.W. Hollmann, J.J. van Lieshout, o r a l p r e s e n tat i on

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The Advanced Trauma Life Support in severely burned patients is associated with an increase in mechanical ventilation and complication rate


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D.S. Veldhuijzen, A.J.M. van Wijck, R. Geenen, J.W.G. Jacobs, C.J. Kalkman poster walk around groep 1

F.B. van Dehn, D.P. Mackie, P. Knape, C. Boer

F. de Lange, J. Karhausen, B. Phillips-Bute, M. Swaminathan, B. Mackensen

Shock induced stress induces loss of microvascular endothelial Tie2 in the kidney

Contribution of S(+)-norketamine to S(+)-ketamine effect on cardiac output in a cross-over study in healthy volunteers



p o s t e r d i s c u s s i o n

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I.M. Noppers, F.K. Mouton, A.M. Morariu, E. Olofsen, R.A.G. Mooren, E.Y. Sarton, A. Dahan

M. Kox, J.C. Pompe, M. Vaneker, L.M. Heunks, J.G. van der Hoeven, C.W. Hoedemaekers, G.J. Scheffer, P. Pickkers


Effects of sympathetic arousal and interoceptive awareness on pain in fibromyalgia: a feasibility study

T. Harendza, J. Larmann, U. Maus, F. Echtermeyer, G. Theilmeier poster walk around groep 1


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Syndecan-4 modulates inflammation in ALI

E. Kortekaas, B. Jaiswal, K. Ruh, G.P. Foster, J.D. Anholm, J.C. de Graaff


poster discussion

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R. Deumens, R.J.P. Jaken, M.A.E. Marcus, E.A.J. Joosten poster walk around groep 1 15

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Spinal cord stimulation reduces the neuronal metabolism of the superficial dorsal horn (DH) after spinal cord stimulation (SCS) in rats with nerve injury induced pain. (preliminary data) H. Smits, T. Pederzani, J.L.M. Jongen, E.A.J. Joosten, F. Huygen

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augustus '09 nederlands tijdschrift voor anesthesiologie

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p o s t e r wa l k a r ound groep 1

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M.C.A. Boom, E. Olofsen, D. Nieuwenhuijs, L. Teppema, A. Dahan

J.W.H. Hol, D.F. Fekkes, C Heijmas-Antonissen, F. Zijlstra, M. Klimek, R.J. Stolker 24


High prevalence of lifestyle risk factors in the surgical population

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Renal microvascular endothelial activation in a mouse model of hemorrhagic shock: is the neutrophil a key player in organ dysfunction?


F.M. Wulfert, M. van Meurs, N.F. Kurniati, R.M. Jongman, J.G. Zijlstra, M.M.R. Struys, G. Molema

Chronic post-surgical pain: Is there a role for epidural anesthesia and analgesia in the prevention? H.M.S. Theunissen, E.A.C. Bouman, M.L. Peters, H.F. Gramke, M. van Kleef, M.A.E. Marcus

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K.M. Szadek, S. Ustymenko, S.A. Loer, W.W.A. Zuurmond, R.S.G.M. Perez


Anti-inflammatory treatment for Complex Regional Pain Syndrome type-1 (CRPS-1): a meta-analysis

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Perioperative alterations in the stress imprint in human plasma lead to the induction of pro-apoptotic and stress markers in cardiomyocytes K.W.L. van Deutekom, J.R. de Jong, J.W.A. Romijn, H.W.M. Niessen, C. Boer

S.G.L. Fischer, R.S.G.M. Perez, S.A. Loer, W.W.A. Zuurmond


Role for toll like receptor-4 in ventilatorinduced diaphragm dysfunction in mice

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Cardiac Output monitoring in cardiac surgery: invasive versus non-invasive

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Measurement of perioperative changes in the pulse pressure variation in spontaneously breathing patients T.A. van Veelen, D.C. Hooijberg, K. Treskes, D.P. Veerman, C. Boer


Thrombomodulins lectin like domain (LeD) alters outcome and inflammation in a murine CLP mouse model

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Prehospital endotracheal intubation does not associate with outcome in patients with severe traumatic brain injury G. Franschman, S.M. Peerdeman, T.M.J.C. Andriessen, S. Greuters, G.N. Jukema, S.A. Loer, C. Boer poster walk around groep 1

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The effects of implementing a new schedule at the preoperative assessment clinic G.M. Edward, B. Preckel, B.S. Martijn, F.J. Oort, J.C.J.M. De Haes, M.W. Hollmann poster walk around groep 1

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Pulse transit time during induction by a propofol bolus V. Rezvani, M. Reekers, F. Boer, A. Dahan, J. Vuyk poster walk around groep 1

T.A.J. Lohuis, N. Tajaate, N.A.H. Helgers, H.M.S. Theunissen, M.A.E. Marcus, M.D. Lance

W.J.M. Schellekens p o s t e r wa l k a r ound groep 1

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Evaluation of different blood drawing tech niques on the results of platelet function tests

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N.H.A. Lecluse, R.L.O. v.d. Laar, J.P. Hering, C. Boer poster walk around groep 1

F.H. Tijssen, Y.M.C. Henskens, H.M.S. Theunissen, R. van Oerle, K. Hamulyak, H. ten Cate, M.A.E. Marcus, M.D. Lance

The inter-examiner reliability of pressure algometry for the region of sacroiliac joint



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A. Lukas, R.G.S.M. Perez


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The impact of surgery on nitric oxide and its associated cytokine and amino acid biochemical pathways

Pulsed radiofrequency treatment for postmastectomy pain



Remifentanil-propofol interaction on spontaneous respiration in healthy volunteers tested under open-loop conditions

A.M. Morariu, M. Swartjes, L.P.H.J. Aarts, A. Dahan


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inhoud

Erythropoietin-like peptides protective role in neuropathic pain?


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Application of microarray-based gene expression technology to malignant hyperthermia M.S. Snoeck, J.C.F. Koenen, E. Sterrenburg, S. van der Maarel

T. Harendza, T. Barkhausen, F. Echtermeyer, G. Theilmeier

opinion

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Scientific misconduct in anesthesia research: no exception to the rule J.W. van Kleef, J. Loadsman, S. Shafer, A. Dahan

Young Investigators Grant 2007

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Opioïd-geïnduceerde hyperalgesie ontstaat onafhankelijk van opioïdreceptor-activatie E.Y. Sarton


09-09-09 11:01

Advertentie

Het orthopediecentrum van de Sint Maartenskliniek telt ruim 400 medewerkers. De orthopeden, anesthesiologen en radiologen werken integraal met elkaar samen aan de diagnose en behandeling van onze patiënten. De formatie van de staf anesthesiologie telt 10,85 fte. Om kwaliteitszorg te kunnen bieden met het best haalbare resultaat voor de patiënt is een bewuste keus gemaakt voor een differentiatie in aandachtsgebieden. Het ziekenhuis heeft een NEN-ISO 9001-2000 certificering voor onder meer bloedmanagement, pijnbestrijding en neuromodulatie. Verbetercycli en research zijn een integraal onderdeel van onze zorgactiviteiten. Steeds meer patiënten vinden hun weg naar de Sint Maartenskliniek. Wij huldigen de stelling dat je het beste leert door anderen te leren en hebben derhalve plaats voor een

Fellow anesthesiologie m/v De functie U werkt als anesthesioloog en krijgt de kans zich verder te bekwamen op een aantal van de bovengenoemde terreinen. Het fellowship is vooral gericht op het verwerven van expertise op het gebied van de locoregionale anesthesietechnieken, met name de (echogeleide) perifere zenuwblokkades. Van de fellow wordt participatie in lopend wetenschappelijk onder zoek verwacht. Deelname aan een internationale cursus en bezoek aan regionale anesthesiecongressen maken deel uit van het fellowship.

Wij vragen Jonge, ambitieuze en enthousiaste anesthesiologen die hun vak goed beheersen en zich graag willen bekwamen in de locoregionale anesthesie. U onderschrijft onze doelstellingen: tevreden patiënten, veilige en efficiënte zorg. U bent een medewerker die verantwoordelijkheid neemt en u communiceert vlot op verschillende niveaus.

Wij bieden Een prachtige functie, waarin u zich kunt ontwikkelen in een deelgebied van de anesthesiologie. Deze functie biedt jonge collega’s het fundament voor een mooie carrière in of buiten de Sint Maartenskliniek. De Sint Maartenskliniek stuurt op kwaliteit, service en snelle doorstroomtijd en richt zich op prestaties en groei van de medewerkers en de organisatie. Arbeidsvoorwaarden conform de eigen AMS+-regeling inclusief budget voor cursus- en congresbezoek, dienstverband van één jaar.

Informatie en sollicitatie Voor nadere informatie kunt u contact opnemen met Dr. R. Stienstra, medisch hoofd anesthesiologie, telefoon (024) 365 92 96. Uw schriftelijke sollicitatie kunt u vóór 5 oktober a.s. richten aan de dienst Personeel & Organisatie, t.a.v. drs. P. de Booys, senioradviseur P&O, Postbus 9011, 6500 GM Nijmegen, onder vermelding van vacaturenummer 93/2009. Solliciteren per e-mail kan ook: [email protected]. Acquisitie naar aanleiding van deze advertentie wordt niet op prijs gesteld.

Sterk in beweging


09-09-09 11:01


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colofon Het Nederlands Tijdschrift voor Anes thesiologie is het officiële orgaan van de Nederlandse Vereniging voor Anesthe siologie. Het stelt zich ten doel om door middel van publicatie van overzichts artikelen, klinische en laboratorium studies en casuïstiek, de verspreiding van kennis betreffende de anesthesi ologie en gerelateerde vakgebieden te bevorderen. REDACTIE

Kernredacteuren: Prof. Dr. L. Aarts, Dr. C. Boer, Prof. Dr. A. Dahan, Dr. H. van Dongen, Prof. Dr. S. de Hert, Dr. M. Klimek, Prof. Dr. J. Knape, Prof. Dr. M.A.E. Marcus, Prof. Dr. G. Scheffer. Ondersteunend redacteuren: Drs. M. van der Beek, Drs. E. Bouman, Dr. P. Bruins, Drs. G. Filippini, Dr. D. Gommers, Prof. Dr. M. Hollmann, Dr. W. Klei, Dr. A. Koopman, Prof. Dr. S. Loer, Drs. S. Schiere, Dr. R.J. Stolker, Dr. B. in het Veld, Dr. K. Vissers, Drs. E. Wiewel. Secretaresse: mw. W. van Engelshoven Voor informatie over adverteren en het reserveren van advertentieruimte in het Nederlands Tijdschrift voor Anesthesiologie: Mw W. van Engelshoven e-mail: [email protected]

REDACTIE-ADRES

Nederlands Tijdschrift voor Anesthesiologie, mw. W. van Engelshoven, Academisch Ziekenhuis Maastricht, Afdeling Anesthesiologie, Postbus 5800, 6202 AZ Maastricht; [email protected] internet: www.anesthesiologie.nl

INZENDEN VAN KOPIJ

Richtlijnen voor het inzenden van kopij vindt u op www.anesthesiologie.nl of kunt u opvragen bij de redactie of de uitgever.

OPLAGE 2.500 exemplaren, 4x per jaar Het NTvA wordt uitsluitend toegezonden aan leden van de NVA. Adreswijzigingen: Nederlandse Vereniging voor Anesthesiologie, Postbus 20063, 3502 LB Utrecht, tel. 030-2823385, fax 030-2823856, e-mail [email protected]

PRODUCTIE

Bladcoördinatie: Drs. Thomas Eldering (023-5259332) Ontwerp: Dimitry de Bruin Eindredactie: Monique de Mijttenaere

AUTEURSRECHT EN AANSPRAKELIJKHEID

© De Stichting tot Beheer van het Nederlands Tijdschrift voor Anesthesiologie 2009. Nederlands Tijdschrift voor Anesthesiologie® is een wettig gedeponeerd woordmerk van de Nederlandse Vereniging voor Anesthesiologie. Alle rechten voorbehouden. Niets uit deze uitgave mag worden verveelvoudigd, opgeslagen in een geautomatiseerd gegevensbestand of openbaar gemaakt, in enige vorm of op enige wijzen, hetzij elektronisch, mechanisch, door fotokopieën, opnamen of enige andere manier, zonder voorafgaande schriftelijke toestemming.


editorial

Wetenschappelijk onderzoek

Prof. dr. S.A. Loer Voorzitter commissie Wetenschap Afdeling Anesthesiologie VU Medisch Centrum Amsterdam [email protected]

Investeren in talenten

W

etenschap kan worden beschreven als geordende kennis van de werkelijkheid. Deze kennis wordt verworven door systematisch wetenschappelijk onderzoek met behulp van specifieke methodes zoals gestructureerde observatie of zorgvuldig opgezette experimenten. Uiteindelijk is het doel om met precisie en objectiviteit de lacunes in onze kennis op te vullen en onze dagelijkse praktijkvoering wetenschappelijk te onderbouwen. De anesthesiologie en perioperatieve geneeskunde bieden zeer interessante perspectieven voor wetenschappelijk onderzoek. Anesthesiologen observeren en beïnvloeden een groot aantal fysiologische - meestal vitale - lichaamsfuncties. Er zijn echter nog talloze lacunes op het gebied van de perioperatieve geneeskunde; lange termijn effecten van een algehele anesthesie zijn nog weinig onderzocht. Om wetenschappelijk onderzoek te realiseren hebben we ambitieuze talenten nodig, die de academische uitdaging zoeken. Deze moeten we actief zoeken en faciliteren. Helaas is ons specialisme tijdens de opleiding tot basisarts weinig zichtbaar, vooral voor jonge talenten. Sommige van hen realiseren te laat of helemaal niet dat anesthesiologie een veelzijdig en interessant vak is. Naast het aantrekken van talenten speelt het faciliteren een belangrijke rol. De Young Investigator Grant 2009 die jaarlijks door de Nederlandse Vereniging voor Anesthesiologie aan jonge gepromoveerde onderzoekers uitgereikt wordt is een voorbeeld hiervan. In essentie gaat het erom deze talenten een duidelijk academische perspectief te bieden, hier hebben we nog huiswerk te doen. Een cruciaal onderdeel van wetenschappelijk activiteit is het openbaar maken van onze onderzoeksresultaten voor anderen, bijvoorbeeld in de vorm van een

wetenschappelijke presentatie of publicatie in een wetenschappelijk tijdschrift. Zonder openbaarheid heeft wetenschappelijk onderzoek geen toegevoegde waarde voor collegae, de maatschappij, en vooral voor onze patiënten. Als landelijk platform heeft de Nederlandse Vereniging voor Anesthesiologie dit jaar voor de zesde keer de wetenschapsdag georganiseerd. Deze dag is bedoeld om onderzoekers en alle geïnteresseerden de mogelijkheid te geven onderzoeksresultaten aan elkaar te presenteren en te bediscussiëren. Het is goed om een stijgende lijn in de kwaliteit van de ingezonden abstracts te zien. Het is ook goed dat meer en meer collegae belangstelling tonen voor wetenschappelijk onderzoek binnen de anesthesiologie. De redactie van het Nederlands Tijdschrift voor Anesthesiologie heeft daarom besloten in deze editie de abstracts van de Wetenschapsdag van de Nederlandse Vereniging voor Anesthesiologie af te drukken om u een overzicht van het brede spectrum aan actuele onderwerpen te bieden. In deze editie hebben we ook een artikel over wetenschapsfraude opgenomen. Hierin worden voorbeelden beschreven van het zondigen tegen precisie en objectiviteit door het manipuleren of zelfs verzinnen van data. Van Kleef et al. maken duidelijk dat wetenschapsfraude negatieve consequenties voor het vak, de scientific community, de onderzoeker maar vooral ook voor onze patiënten kan hebben. Het is een uitdaging om de aantrekkelijkheid en zichtbaarheid van ons vak zo groot mogelijk te maken. Hierdoor kunnen wij de competitie aan met andere specialismen voor het aantrekken van jonge talenten voor anesthesiologisch wetenschappelijk onderzoek. Ik wens u veel plezier met het lezen van deze editie van het NTvA.

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abstracts oral presentat i o n

Effects of high altitude hypoxia and iloprost on right ventricular function in healthy volunteers E. Kortekaas1 B. Jaiswal2 K. Ruh2 G.P. Foster3 J.D. Anholm3 J.C. de Graaff1 1 Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands 2 Loma Linda University, Loma Linda, USA 3 VA Loma Linda Healthcare System, Loma Linda, USA

Caption 1. Results

Introduction

Results

Conclusion

Ascent to high altitude (HA) reduces exercise capacity due to the fall in arterial oxygen pressure and possibly impaired ventricular function. Left ventricular function is normal or minimally altered at HA. Less is known about the effects of prolonged hypoxia on right ventricular (RV) function. Hypoxic pulmonary vasoconstriction (HPV) at HA may contribute to altered RV function. If HPV contributes to RV dysfunction, then inhaled iloprost, a prostacyclin analogue used in the treatment of pulmonary hypertension, may improve RV function.

Saturation and TAPSE were significantly decreased at HA compared with SL. Inhalation of iloprost did not change significantly either of these measurements. TI peak velocities were significantly lower at HA than at SL after placebo, however we did not observe a significant difference after inhalation of iloprost.

A decrease in TAPSE and TI peak velocities suggests that RV systolic and diastolic function is impaired after a prolonged stay at HA. This is probably caused by hypoxic pulmonary vasoconstriction. However, inhalation of a single dose of iloprost did not reverse these changes in RV function.

Objective To determine the effects of altitude hypoxia and iloprost on RV systolic and diastolic function in healthy volunteers.

Methods A randomized, double blind, cross-over trial of 12 healthy volunteers who participated in the Medex 2008 Expedition to Dhaulagiri, Nepal. Transthoracic echocardiography was performed after placebo and inhaled iloprost (5 microgram), at sea level (SL) and after a 14 day trek to HA at 5050m. Systolic function was assessed by Tricuspid Annular Plane Systolic Excursion (TAPSE). Diastolic function was assessed by tricuspid inflow (TI) E and A wave velocities and tissue Doppler imaging (TDI) of RV free wall of the tricuspid annulus. Additional measurements of SpO2, mean arterial pressure (MAP) and heart rate (HR) were recorded. Measurements were analyzed by paired sample t-test.


Caption 2. Research at 5050m altitude

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oral presentations

oral presentat i o n

The selective a7nAChR agonist GTS-21 attenuates ventilator-induced inflammation and lung injury M. Kox J.C. Pompe M. Vaneker L.M. Heunks J.G. van der Hoeven C.W. Hoedemaekers G.J. Scheffer P. Pickkers Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Introduction Mechanical ventilation (MV) induces an inflammatory response that contributes to lung injury. The efferent vagus nerve can limit the inflammatory response via the α7 nicotinic acetylcholine receptor (α7nAChR), the so-called cholinergic antiinflammatory pathway. The aim of this study was to evaluate the effect of the selective α7nAChR agonist GTS-21 on inflammation and lung injury induced by MV using clinically relevant ventilator settings.

Methods C57BL6 mice (n=40) were i.p. injected with 8 mg/kg GTS-21 or placebo following mechanical ventilation for 4 hours (tidal volume 8 mL/kg; PEEP 1.5 cm H2O; FiO2 0.45). Unventilated mice were used as controls. Arterial blood gases were obtained at the end of the experiment and TNF-α, IL-6, IL-1β, KC and IL-10 were determined in plasma and lung homogenates. Lung TNF-α and IL-10 mRNA expression was measured in lung homogenates using quantitative PCR.

(196.2±50.8 vs. 331.9±31.9 pg/mL; p=0.04). Similarly, in lung homogenates a distinct trend was observed towards lower TNF-α levels in GTS-21-treated mice (53.9 ± 12.5 vs. 79.1 ± 5.6 pg/mg protein; p=0.06). IL-10 levels were unaffected by GTS-21. MV strongly increased TNF-α mRNA expression in lungs of placebo animals (21-fold compared to controls), this was significantly lower in GTS-21-treated mice (12-fold compared to controls; p=0.02). IL-10 mRNA expression was similar in GTS-21-treated and placebo animals.

Results

Conclusion

In GTS-21-treated mice, the alveolar-arterial (A-a) gradient after MV was significantly reduced compared to placebo (18.7± 0.8 vs. 20.8 ± 0.6 kPa; p=0.04). MV resulted in an increase of all cytokines in plasma and lung compared to control mice. TNF-αwas significantly lower in plasma of GTS-21treated animals compared to placebo

GTS-21 inhibits pro- but not anti-inflammatory cytokine production induced by MV. The reduced A-a gradient in GTS-21treated animals indicates attenuation of lung injury. The cholinergic anti-inflammatory pathway may represent new treatment options for MV-induced lung injury.


Left ventricular ejection fraction assessed by 2D and 3D echocardiography: Does experience matter? F. de Lange J. Karhausen B. Phillips-Bute M. Swaminathan B. Mackensen Duke University Medical Center, DURHAM, USA

Introduction The perioperative assessment of ejection fraction (EF) is an important tool to describe global LV function by visually categorizing EF into six clinically distinct ranges. Three-dimensional TEE (3D-TEE) however offers a quantitative assessment of EF. Although higher levels of experience may yield clinically acceptable reliability


regardless of the approach, this has not been studied yet. Therefore, we evaluated the intra-observer reliability and the interobserver agreement of 2D and 3D-TEE assessments of EF, each performed by a novice and experienced echocardiographer.

Methods After IRB approval, 3D full volume and standard 2D-TEE loops assessing LV function from 50 patients undergoing cardiac surgery were assessed twice offline by a novice and an experienced echocardiographer. 2D-TEE EF was visually estimated based on six ordinal categories (<15%, 1525%, 25-35%, 35-45%, 45-55%, >55%). Using available built-in software, 3D-TEE EF

was quantified numerically. On these data, Spearman and Pearson correlation and Bland-Altman analyses were performed.

Results Intra-observer reliability was high for both observers for the 2D (r=0.87 and r=0.90) and 3D assessment (r=0.93 and r=0.91). Inter-observer correlation for 2D and 3D assessment was r=0.70 and r=0.78 respectively. Bland-Altman analysis of the 2D-TEE assessments revealed a directional observer bias in that the experienced observer tended to rate the EF higher than the novice by almost one category (Figure A). This difference gets larger as the EF values increase. For the 3D assessment

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abstracts 2009 Bland-Altman analysis revealed no directional observer bias (Figure B).

Conclusion Novice and experienced observers can reproducibly determine EF with either method. There was reasonable correlation between observers in both ratings. However, the 2D-TEE assessment revealed an observer bias towards the experienced observer rating the LVEF higher. This information suggests that assessment based on 3D-TEE data may offer a more reliable quantification, especially for less experienced users. Figure A

Figure B


Cerebral autoregulation is unaltered by sympathetic denervation with stellate ganglionic blockade R.H.A. Passier1 R.V. Immink1 J. Truijen1 J.H. Vranken2 M.H. van der Vegt3 M.W. Hollmann1 J.J. van Lieshout1 1 AMC, Amsterdam, the Netherlands 2 Medisch Centrum Alkmaar, Alkmaar, the Netherlands 3 Rode Kruis Ziekenhuis, Beverwijk, the Netherlands

Introduction Cerebral autoregulation (CA) is a complex of fast and slow regulatory mechanisms that maintain a constant cerebral blood flow (CBF) during changes in mean arterial pressure (MAP). Cerebral arteries are innervated by sympathetic fibers but whether sympathetic activity affects the CA in humans is debated. We questioned whether CA is modulated by an increase


in sympathetic activity elicited by postural stress in subjects with a sympathetic denervated cerebral hemisphere by unilateral superior stellate ganglion blockade (SGB).

Methods In seven patients treated with a SGB for their chronic pain complaints, non-invasive beat-to-beat finger blood pressure (Finometer), middle cerebral artery blood velocity (MCA Vmean; transcranial Doppler) and frontal cerebral oxygenation (FCO; near infrared spectroscopy) were monitored bilaterally in the supine and upright position. Slow acting regulatory mechanisms of CA were quantified by analyzing the difference in MCA Vmean during different steady state levels of MAP at brain level in the supine and upright position. Fast acting regulatory mechanisms of CA were quantified by analyzing the MCA Vmean to MAP phase lead by Fast Fourier Transform during 0.1 Hz spontaneous oscillations in MAP in the supine and upright position.

Results During SGB, tilting decreased MAP at brain level from 87±5 to 78±8mmHg (mean±SEM; p<0.05). Phase lead decreased from 48±8º to 40±8º (blocked) and from 47±8º to 40±7º (contra-lateral; all p=NS). The postural decrease in MCA Vmean was 9.2±9.1% vs. 9.9±7.6% and cerebral oxygenation 2.8±2.3% vs. 2.4±2.3% in the blocked and contra-lateral hemisphere respectively (all p=NS).

Conclusion In patients with one sympathetic blocked cerebral hemisphere by GSB, an increase of systemic activity by tilting does not alter MCA Vmean or FCO. Assuming GSB causes ipsilateral cerebral sympathetic denervation implies the sympathetic nervous system is not a significant contributor to the regulatory mechanisms of CA analyzed in this study.

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oral presentations


Effect of N-methyl-D-aspartate receptor(NMDA-R) antagonists in a rat model of neuropathic pain M. Swartjes A. Dahan A.M. Morariu

LUMC, Leiden, the Netherlands

Introduction The important role of NMDA-R in the development and maintenance of chronic pain states has been well documented in the scientific literature. NMDA-R antagonists have shown efficacy in preclinical models as well as in patients with neuropathic pain (NP). A large-scale clinical use of NMDA-R antagonists is limited due to unacceptable side effects (hallucinations, sedation, ataxia) of currently available compounds of this class (Ketamine). More recently, a new compound Traxoprodil has been described as a potent, selective NR2B (subunit of NMDA-R) antagonist with proved neuroprotective effects in both animal models of brain ischemia and patients with traumatic brain injury. This study aims to investigate the therapeutic value of Traxoprodil in a rat model of NP (Spared Nerve Injury - SNI model) as compared to Ketamine.

Methods The SNI model is demonstrated to be robust and give prolonged neuropathic pain states (>90 days) with pain-behavior modifications (paw inversion, allodynia,


Figure 1

hyperalgesia). The drugs were titrated to a dose that gave significant analgesia with tolerable side effects (Ketamine i.v. 3 mg/ kg/hour, Traxoprodil 20 mg/kg/hour for 3hours, 5 consecutive days). The response to tactile/cold allodynia and thermal/ mechanical hyperalgesia was assessed. Side effects were scored and registered.

for 24±6 POD, Traxoprodil for 30±1POD (Figure 1). While Ketamine treatment was accompanied by important side effects (psychotic behavior-locomotor hyperactivity, head waving, overflow incontinence), there was no evidence of any side effects during Traxoprodil treatment.

Results

NMDA-R antagonists prove to be effective therapeutic drugs against mechanical allodynia, in this model of neuropathic pain. Traxoprodil exhibited a superior therapeutic index for efficacy versus psychotomimetic side effects.

Both NMDA-R antagonists significantly reduced tactile allodynia in rats with neuropathic pain. However, no effects were observed on heat/mechanical hypersensitivity. Ketamine relieved tactile allodynia

Conclusion

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abstracts 2009 oral presentation

Molecular diagnosis of RYR1 gene mutations causative for susceptibility to malignant hyperthermia and/or central core disease using the MLPA method M.S. Snoeck J.C.F. Koenen Y. Aardsen C. Klaasen Canisius-Wilhelmina Ziekenhuis, Nijmegen, the Netherlands

individuals who are members of IVCTtested European MH families in which a causative mutation has been detected by using currently available methods and on samples from individuals that have been tested in Nijmegen by the IVCT from 2006 untill 2009.

tations control DNA had been lacking. In 35 MHS tested individuals from 12 families, 6 mutations were detected without discordance. In 6 MHE tested individuals (5 families) no mutations have been detected. In an MHN tested mother from an index patient we found the A7025G mutation that we had detected in the index!

Introduction

Methods

In 2002, the multiplex ligation-dependent probe amplification (MLPA) technique was introduced [1]. MLPA is basically a method to make a nucleic acid sample suitable for a multiplex PCR reaction in which up to 45 specific sequences are amplified simultaneous with the use of only one pair of PCR primers.

MRC-Holland composed an improved kit of 2 mixes (salsa MLPA KIT P281 / P282 TM), containing 33 RYR1 mutations. 3 of the 29 ‘EMHG-causative mutations [2] could not be incorporated because of technical problems; 7 frequently occurring mutations made up the total of 33.

Conclusion

Results

The aim of this study was to test the MLPA method on control DNA samples from 24

23 mutations could be confirmed by MLPA, 1 could not be detected (G7361A); for 9 mu-

references 1. J.P. Schouten et al, 2002, Nucleic Acids Res.; 30, e57. 2. WWW.EMHG.Org. 3. A. Urwyler et al, 2001, Br J Anaesth.; 86: 283-287.

The method is easy to handle, fast, cheap, reproducible and as the assay only requires commonly used technology, it can easily be implemented in a diagnostic MH laboratory for genetic screening [3].

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Onderdeel The Surgical Company Group te Amersfoort

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poster discussi o n

Shock induced stress induces loss of microvascular endothelial Tie2 in the kidney F.M. Wulfert M. van Meurs N.F. Kurniati R. M. Jongman J.G. Zijlstra M. M. R. Struys G. Molema UMCG, Groningen, the Netherlands

Introduction Acute kidney injury after shock states is a complication of hemorrhagic and septic shock. Both hemorrhagic shock and endotoxaemia induce a pronounced vascular activation in the kidney which coincides with albuminuria. We hypothesized that changes in Tie2, a vascular restricted endothelium receptor tyrosine kinase shown to control microvascular integrity and endothelial inflammation, underlie this loss of glomerular barrier function.

Method For induction of HS, male C57Bl/6 anesthetized mice were subjected to controlled HS with a MAP of 30 mmHg during 90 minutes followed by resuscitation with 6% HES. For the induction of endothoxaemia, mice were injected(i.p.) with LPS. After 4, 8, or 24 hours

post volume resuscitation or LPS injection mice were sacrificed under isoflurane. In selected animals, neutrophil depletion was established by intraperitoneal injection of anti-NIMP antibody 24 hour prior to HS or endothoxaemia induction. mRNA expression of Tie2 and E-selectin was measured in kidney by real time RT-PCR. Protein expression of Tie2, E-selectin, and CD45 was measured by immunohistochemistry and ELISA. mRNA and protein expression was compared to expression in non-treated counterparts. Micro-albuminuria, as a measure of glomerular barrier function, was measured in mouse urine using a commercial available kit.

Results

and temporarily, lost from the renal microvasculature, and normalized after 24 hours. In parallel to the loss of Tie2 in vivo, an overt influx of neutrophils in the glomerular compartment which coincides with proteinuria, was seen. While neutrophil depletion abolished proteinuria (figure A), Tie-2 was not rescued (figure B).

Conclusion The observed rapid and temporary loss of Tie2 in reaction to hemorrhagic shock and LPS mediated endotoxaemia could not be directly related to the occurrence of proteinuria, and therewith to diminished glomerular barrier function.

In mice subjected to hemorrhagic and septic shock, Tie2 mRNA and protein were rapidly,

poster discuss i o n

Syndecan-4 modulates inflammation in ALI T. Harendza1 J. Larmann1 U. Maus2 F. Echtermeyer2 G. Theilmeier1 Medizinische Hochschule Hannover, Hannover, Germany 1 Department of Anaesthesiology and Intensive Care Medicine, Experimental Anaesthesiology, Hannover Medical School, Germany 2 Department of Pneumology; Laboratory for Experimental Lung Research, Hannover Medical School, Germany

Introduction The lethality of acute pulmonary inflammation remains high because the pathophysiology is incompletely understood. Intratracheal instillation of lipopolysaccharide (LPS) leads to a 40-fold increased expression of Syndecan-4 (Syn4) in macrophages and Syn4 deficiency causes excess mortality in endotoxic shock. We examined this molecules role in


LPS-induced ALI in Syn4-deficient (Syn4-/-) and wild-type mice (WT).

Methods LPS was intratracheally instilled in isoflurane (in air) anaesthetized Syn4-/--and WT-mice. After 24h arterial blood gas analysis and BALF were performed. Lungs were either snap frozen and homogenized for rtPCRs or kryo-embedded for immunehistochemical evaluation. Transendothelial migratory capacity of bone marrow derived PMNs was examined in a transmigration assay.

Results Pulmonary LPS instillation in Syn4-/-mice led to lower arterial pO2 (107.2±27 vs.142±15.8mmHg, n=8, p<0.05) and aggravated lactic acidosis (9.06±3.69 vs. 6.33±1.93, n=8). IL-6 and TNFα expression was elevated 1.4- and 8-fold (n=8) in Syn4-/- lungs. Whilst

there were no intra-alveolar differences between both groups, Syn4-/--lungs had 2-fold more PMNs (124.7±15.4 vs. 59.6±11;p<0.05). Macrophage content of BALF increased 1.6-fold, while monocyte counts in lung tissue were 3-fold higher in Syn4-/- (9±2.2 vs. 2.9±0.9(WT); p<0.05). rtPCR demonstrated a 52% reduced ICAM-1 expression. Transmigratory capability of Syn4-/--PMNs through activated endothelial cells was less than 50% of WT-PMNs.

Conclusion LPS instillation in Syn4-/- leads to pulmonary accumulation of leukocytes and cytokines. The discrepancy between increased leukocyte recruitment into the lung and reduced leukocyte transmigration to the alveoli suggests a potential role of Syn4 in endothelial transmigration processes. Syn-4 could be a therapeutic target in ALI.

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Contribution of S(+)-norketamine to S(+)-ketamine effect on cardiac output in a cross-over study in healthy volunteers I.M. Noppers F.K. Mouton A.M. Morariu E. Olofsen R.A.G. Mooren E.Y. Sarton A. Dahan LUMC, Leiden, the Netherlands

Introduction S(+)-ketamine has a stimulating effect on the cardiac output due to its sympathicomimetic properties. S(+)-ketamine is metabolized in the liver into S(+)-norketamine which is considered an active metabolite. The contributing effect of S(+)-norketamine on the cardiac output is the topic of the current study.

Methods This prospective randomized cross-over placebo-controlled study was conducted

in healthy male volunteers. To study the effects of S(+)-norketamine, rifampicin was used to induce metabolic activity (via CYP3A4) within the liver. Subjects were tested twice, after a 5 day rifampicin pretreatment and after a 5 day placebo pretreatment (pre-treatment was randomised). On both occasions S(+)-ketamine was administered intravenously for 2 hours at a rate of 20 mg.70kg-1.h-1 During the infusion and 3 hours thereafter, cardiac output was measured using the FloTrac sensor connected to an arterial line and a Vigileo monitor. At regular intervals arterial blood was sampled to measure S(+)- ketamine and S(+)-norketamine plasma concentrations.

Cardiac output increased rapidly after the start of the S(+)-ketamine infusion. The increase in cardiac output was 20-30% larger after rifampicin pre-treatment.

Conclusion The data show that during S(+)-ketamine infusion, a reduction in S(+)-norketamine concentration (but similar S(+)-ketamine concentrations) causes a larger increase in cardiac output. This indicates that S(+)-norketamine has a reverse effect on cardiac output compared to S(+)-ketamine. Possibly, S(+)-norketamine has symathicoinhibitory properties.

Results S(+)-ketamine plasma concentrations were similar after placebo and rifampicin pretreatment. However, S(+)-norketamine concentrations were significantly reduced (by > 50%) after rifampicin pre-treatment.

poster walk ar o u n d g r o e p 1

The Advanced Trauma Life Support in severely burned patients is associated with an increase in mechanical ventilation and complication rate F.B. van Dehn1 D.P. Mackie2 P. Knape2 C. Boer1 1 VU Medical Center, Amsterdam, the Netherlands 2 Red Cross Hospital, Beverwijk, the Netherlands

The introduction of Advanced Trauma Life Support (ATLS) in severely burned patients aimed for improved care and a reduction in morbidity and mortality in this specific patient population. We investigated whether the introduction of ATLS indeed improved clinical care and outcome in severely burned patients.


The medical records of 258 consecutive patients with burns of >30% total body surface area (TBSA), who were admitted to the burn centre from January 1987 to December 2006 were retrospectively analyzed and included in a database. Patients were divided into two groups, based on admission date: 1) from 1987 to 1996 (n=135) and 2) from 1997 to 2006 (n=123). Data were analyzed using Chi-square, ANOVA or regression analysis. Both groups did not differ in baseline values including sex, age, gender, weight at

admission, facial burns, the %TBSA and the incidence of inhalation injury. However, the relative number of mechanically ventilated patients at day 0 post-burn doubled from 38% to 76% (P<0.001). Moreover, the increase in mechanical ventilation in the post-ATLS group was associated with an increase in mortality (9 vs.17 casualties in group 1 and 2; P=0.05), the incidence of respiratory complications (2 vs.17 patients; P=0.01) and the need for inotropic support (4 vs.56 patients; P=0.04). A closer evaluation of the outcome in ventilated patients versus spontaneous breathing victims re-

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vealed that ventilation was associated with an increased fluid balance on day3 and 7 (both P<0.05) and an increase in patients with sepsis and respiratory complications.

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poster walk around This study shows an apparent increase in mechanically ventilated burn patients after the introduction of ATLS in 1996. The introduction of ATLS in this specific patient pop-

ulation did associate with an increased incidence of complications and mortality. These results warrant a re-evaluation of ATLS as standard care in severely burned victims.


Impact of platelet function analysis on decision making in preeclampsia F.H. Tijssen V.M. Smit-Fun V.C.M.L Timmer A. Kroese M.A.E. Marcus M.D. Lance MUMC+, Maastricht, the Netherlands

Introduction Preeclampsia complicates about 1-2% of all pregnancies. In 10-50% thrombocythopenia occurs. Data on platelet function is rare. This information can be valuable in decision making in respect to choice of anesthesia technique. The aim of the study was to determine thrombocyte function in Preeclamptic patients (P) compared to that in Healthy patients(H) by novel platelet function analysis techniques.

Methods After local institutional approval, we took written informed consent of 28 pregnant

patients (14 H/14 P). Data on demographics, blood pressure, drug/herbal supplement use, and bleeding risks and laboraty values were collected. Venous blood samples were collected in hirudine, citrate and EDTA-tubes. We performed impedance-aggregrometry (multiplate®) with the following activators: ADP at stepwise increasing levels (0,5mmol/ 2,5mmol/ 7,5mmol), thrombine receptor test (TRAP) and collagen, PFA100® analysis with coll/ADP and coll/EPI, platelet count and mean platelet volume measurement (MPV).

Results There were no significant differences with respect to age, gestational age and bleeding risk. Blood pressure and use of antihypertensive drugs differed significantly. For the H versus P groups PFA-100 analysis with coll/ADP vs coll/EPI test showed closure times of 83,8±25,1 vs 86.9±15,4 sec-

onds and 100,8±26,2 vs 116,0±38,2 seconds respectively. With impedance-aggregometry for ADP the mean AUC at 0,5, 2,5 and 7,5 µmol were 33,0 ±24,3 vs 26,9±12,9, 68,0±29,4 vs 72,5±29,1 and 72,2±28,7 vs 88,1±29,6. Collagen and TRAP-test resulted in AUC 98,9±36,4 vs106,4±33,0 and 76,5±29,7 vs 99,6±26,2 (p<0.037). Platelet count was 266.4±79,4 vs 236,1±70,7 and MPV 8,5±1,0 vs 9,4±1,3 (p=0.05).

Conclusion TRAP is significantly higher in P. This could indicate higher thrombine pathway activity. A larger MPV points to higher platelet reactivity. To confirm this thesis and its impact on decision making a larger population has to be studied.


Midazolam premedication for children undergoing T&A? J.M.K. van Fessem1 A.A. van Maris1 R.A.J.M. Willems1 P.G.J. ten Koppel1 A.J.W. Teunissen1 R.J. Stolker2 1 Maasstadziekenhuis, Rotterdam, the Netherlands 2 Erasmus MC, Rotterdam, the Netherlands

Introduction Before undergoing surgery, children exhibit stress and anxiety, which can result in


adverse physiologic and psychological effects. Besides the use of behavioral training methods, children often receive premedication. In this study, the effect of premedication with midazolam on children undergoing adenoidectomy and/or tonsillectomy (T&A) was prospectively investigated and compared with behavioral training.

Methods 192 children (2-10 years, ASA 1,2) presented for T&A were administered 0.5 mg/kg midazolam rectally (n=86) or received

child and parental training before going to OR (n=106). Anesthesia was induced in presence of one parent and the trainer and continued after intubation with sevoflurane. Monitoring was applied according to standard practice. Postoperative medication (acetaminophen, diclofenac) was given according to local protocol. Parents and staff were asked to fill in our questionnaire concerning anxiety (before OR and induction), cooperation, drowsiness during the day of operation, PONV and diet intake back home.

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abstracts 2009 Results Children receiving midazolam were significantly more sleepy during the day, more cooperative in OR and less frightened before going to OR than children without premedication (P = < 0,001, using Chisquare statistical tests). However, there was no difference (P= 0.58) in being frightened at time of induction. The midazolam group suffered slightly more from PONV (P=

0.048), but there were no differences in diet intake (P= 0.30).

Conclusion Although premedicated children were more cooperative and less frightened before undergoing T&A, there was no difference prior to induction. This is possibly a result from preoperative training just before the operation. Since the children with

midazolam are more sedated all day long and suffer more from PONV, premedication can better be omitted and preserved for special cases, if proper non-medical interventions are applied. A larger randomized study should be performed.


Acute pain stress increases phosphorylation of DCLK-long in the rat Edinger-Westphal nucleus but not in the hypothalamic paraventricular nucleus T.P.H. Rouwette1 L.T. Kozicz2 N.F.M. Olde Loohuis2 B. Gaszner3 E. Vreugdenhil4 G.J. Scheffer1 E.W. Roubos2 K.C. Vissers1 W.J.J.M. Scheenen2 1 UMCN, Nijmegen, the Netherlands 2 Department of Cellular Animal Physiology, Nijmegen, the Netherlands 3 Department of Anatomy, PÉCS, Hungary 4 Leiden/Amsterdam Center for Drug Research, Leiden, the Netherlands

Introduction Acute pain stress leads to activation of the stress response, which, in turn, will induce changes in intracellular signaling in two


stress-responsive centers, the paraventricular nucleus of the hypothalamus (PVN) and the midbrain non-preganglionic EdingerWestphal nucleus (npEW). The intracellular signaling pathways that are activated by this pain stressor are unknown. We have explored the possibility that members of the doublecortin-like kinase (DCLK) family of proteins are involved in pain stress-induced signaling in the PVN and the npEW.

Methods Adult male Wistar rats were subjected to an acute pain stress protocol consisting of a formalin injection in the hindpaw and the npEW and PVN were analyzed by immunohistochemistry and Western blotting for the phosphorylation status and intracellular localization of DCLK.

Results Our results show that both DCLK-short and DCLK-long splice variants are present in the cytoplasm and proximal dendrites of neurons in the PVN and the npEW. Of these isoforms, DCLK-long but not DCLKshort is phosphorylated in its serine/proline-rich domain. Furthermore, we demonstrate that phosphorylation of DCLK-long in the npEW is increased by acute pain stress, whereas DCLK-long phosphorylation in the PVN remains unaffected.

Conclusion This is the first report revealing that DCLK isoforms in the PVN and npEW occur in the adult mammalian brain and that the regulatory pathways of DCLK-long differ between these two stress-sensitive brain centers.

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Does a field block reduce the incidence of postoperative pain, nausea and vomiting in oncologic breast surgery? P.M.L.E. Riezebos M.M.J. Snoeck L.J.A. Strobbe

combination with a mamma field block to prevent PONV.

Canisius-Wilhelmina Ziekenhuis, Nijmegen, the Netherlands

In this prospective randomised doubleblind trial a mamma field block was performed under standardized general anesthesia in 84 ASA 1-2 patients scheduled for oncologic breast surgery with either 50 ml of ropivacaine 0,375 % (group A) or 50 ml NaCl 0,9 % (group B). Patients were prophylactic treated with an anti-emetic multimodal regimen using propofol for anesthesia and a combination of dexamethason and droperidol. Postoperative paracetamol and PCA morphine were prescribed. A validated risk score was used to predict the occurrence of PONV. Primary endpoints were pain scores (NRS), opioid consump-

Introduction Breast surgery performed under general anesthesia is associated with a high incidence of postoperative nausea and vomiting (PONV). Prevention strategy, anti-emetic therapy and measures to provide opioid sparing reduce the incidence of PONV. A field block of the breast (mamma field block) might reduce postoperative pain and therefore opioid consumption. The aim of this study was to determine the efficacy of a multimodal approach in

Methods

tion, occurrence of PONV (NRS) and use of rescue anti-emetics throughout the 24 hour study period.

Results The predicted risk score of PONV was 38 % in group A (n=43) and 36% in group B (n=41). There was no difference in pain scores or opioid consumption between the groups. The incidence of PONV was 0 % in group A and 0,07 % in group B. Six patients received a rescue anti-emetic drug.

Conclusion The incidence of PONV using a multimodal regimen was very low. A mamma fieldblock using 50ml ropivacaine 0,375 % had no significant effect on pain scores and opioid consumption.


Effects of sympathetic arousal and interoceptive awareness on pain in fibromyalgia: a feasibility study D.S. Veldhuijzen1 A.J.M. van Wijck1 R. Geenen2 J.W.G. Jacobs1 C.J. Kalkman1 1 UMC Utrecht, Utrecht, the Netherlands 2 Utrecht University, Utrecht, the Netherlands

Introduction Fibromyalgia is characterized by chronic widespread pain. The mechanisms underlying this syndrome remain largely unknown. We hypothesize that awareness of bodily sensations and heightened sympathetic nervous system activity are mediators of pain augmentation in fibromyalgia. A pilot study was performed to test the feasibility and to calculate power for conducting a larger study on the associations between


altered sympathetic nervous system functioning, interoceptive awareness, and pain in fibromyalgia.

Methods In 8 female fibromyalgia patients and 8 matched healthy women, sympathetic nervous system activity was assessed by skin conductance measurements. The individual’s sensitivity to perceive bodily sensations is referred to as interoceptive awareness; it was operationalized by the individual’s ability to accurately perceive one’s heartbeat. Pain thresholds were assessed using a pressure algometer.

Results Patients and healthy controls were able to perform the interoceptive task and to endure the pain measurement. Pressure pain

thresholds were found to be significantly lower for patients compared to controls (1.53 versus 3.66 kg/cm2, respectively; p< 0.001). A trend towards significance was observed for higher interoceptive awareness scores in healthy subjects compared to fibromyalgia patients (0.88 versus 0.74, respectively; p=0.052). In general, higher interoceptive awareness correlated with higher pain thresholds (r = 0.61). Sample sizes were too small to examine this at the subgroup level. No significant effects were found for skin conductance levels. On the basis of this study it could be calculated that a properly powered study to assess differences in skin conductance levels between groups would require 77 participants in each group with a medium effect size (f2=.15), alpha-level of .05, and power of .80.

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abstracts 2009 Conclusion This study demonstrated the feasibility of investigating group differences in pain thresholds as well as interoceptive aware-

ness, while the analyses of differences of autonomic nervous system activity requires a larger sample size.


S(+)-ketamine effect on chronic pain and experimental acute pain in Complex Regional Pain Syndrome type 1 patients M.J. Sigtermans1 J. van Cosburgh2 A. Dahan1 1 LUMC, Leiden, the Netherlands 2 Reinier de Graaf Groep, Delft, the Netherlands

Introduction The aim of the study was to explore the analgesic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS-1) patients.

Methods Ten patients suffering from chronic CRPS-1 and with a Visual Analogue pain

Score (VAS) of > 5 were recruited. Seven intravenous 5-min low-dose S(+)-ketamine infusions with increasing doses at 20-min intervals were applied. Spontaneous pain ratings and VAS responses to experimental heat stimuli were obtained during infusion and for 3-h following infusion. For comparative reasons, the effect of S(+)-ketamine on VAS response to experimental pain was obtained in 12 healthy volunteers.

Results Ketamine produced potent analgesia in patients with a significant VAS reduction from 6.2 ± 0.2 to 0.4 ± 0.3 cm at the end of infusion. Analgesia persisted beyond the infusion period (VAS = 2.8 ± 1.0 cm at 5-h), when measured plasma ketamine concen-

trations were low (< 100 ng/ml). In patients and volunteers, ketamine had a similar dose-dependent antinociceptive effect on experimental pain that ended immediately upon the termination of infusion.

Discussion The data indicate that while ketamine’s effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain.


Fentanyl induces hyperalgesia in humans and mice E.Y. Sarton A. Dahan J. Grefkens B. Kest M. Boom E. van Dorp LUMC, Leiden, the Netherlands

Fentanyl is an opioid frequently used as potent analgesic to treat acute perioperative pain and chronic pain via transdermal applications. There are indications that opioids produce hyperalgesia via pro-nociceptive metabolites. For example, morphine produces hyperalgesia via its two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide. Fentanyl does not have any active metabolites. We therefore tested this opioid in three separate models of analgesia/hyperalgesia.


Model 1. The effect of fentanyl in triple knockout mice (TKO mice devoid of opioid receptors) using a tail immersion test. Model 2. The effect of fentanyl in mice treated with naltrexone using the tail immersion test; Model 3. The effect of fentanyl in humans using heat pain stimuli.

jects were tested in the early hours of the morning (2 AM).

The results indicate potent and long lasting hyperalgesia in TKO mice and control mice treated with naltrexone in both acute and chronic infusion schemes. In contrast, control mice treated with placebo displayed no hyperalgesia.

We further tested the effect of MK801 (an NMD receptor antagonist) in our mice and observed that MK801 effectively prevents development of fentanyl hyperalgesia. Similar observations were made earlier for morphine and M6G. This then suggest that not the opioid receptor but the NMDA receptor is the site of action of opioid hyperalgesia.

In humans analgesia preceded hyperalgesic responses after fentanyl only when the sub-

Our data indicate that a) fentanyl hyperalgesia is not related to opioid-receptor activation, and b) that pronociceptive metabolites are not a prerequisite for opioid-hyperalgesia.

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Paravertebral block for analgesia after major oncologic breast surgery: a comparison of continuous paravertebral block, single shot paravertebral block, and single shot wound infiltration Results

E.A.C. Bouman H.M.S. Theunissen A.G. Kessels M.A.E. Marcus H.F. Gramke Maastricht University Medical Centre + (MUMC+), Maastricht, the Netherlands

Introduction Paravertebral block has been succesfully used for postoperative analgesia after breast surgery. The aim of this study was to evaluate whether a continuous paravertebral block with a catheter technique is superior to single shot paravertebral block or single shot wound infiltration.

Methods 25 patients were included in this prospective, open, randomized controlled trial. Group I received a single shot paravertebral block with 0.25ml/kg ropivacaine 0.75% preoperatively. Group II received a paravertebral block with 0.25ml/kg ropivacaine 0.75% followed by patient controlled paravertebral analgesia with ropivacaine 0.2% during 48 hours. Group III had local wound infiltration with bupivacaine 0.25% at the end of surgery. General anesthesia was provided during surgery to all patients. A 100mm visual analogue scale (VAS) was used for measuring pain intensity. Besides side-effects and complications of anesthesia were recorded.

Overall pain intensity was low in all three groups. VAS-scores were significantly higher in group I compared to group III in the morning and afternoon on the day after the operation (p=0.005 and p=0.021). Except for the first measurement VAS-scores were higher in group III compared to group II, but this difference was only statistically significant on the morning after surgery (p=0.041). We did not record serious sideeffects of any technique.

Conclusion Postoperative analgesia after major breast surgery was succesful in all three groups. Our results do not favour single shot paravertebral block as routine technique for postoperative analgesia after major breast surgery.


Predicting the time course of sensory block after intrathecal injection of lidocaine M.A. Holtkamp1 D.J. Eleveld1 A.M. van Oort1 S. Schiere2 1 UMCG, Groningen, the Netherlands 2 Tjongerschans, Heerenveen, the Netherlands

Introduction Lidocaine is a short-acting local anesthetic frequently used for outpatient procedures. A number of patient and non-patient factors have been suggested to influence the dose-effect relationship of lidocaine, but the relationships are not clear and a wide dose range is used by Dutch anesthesiologists [1]. In this observational study we try to develop a pharmacodynamic model to describe the time course of sensory blockade. We also investigated the incidence of transient neurologic symptoms (TNS).


Methods In this observational study 120 patients were included. All patients received spinal anesthesia with isobaric lidocaine 2%. The technique, dose and needle were chosen by the anesthesiologist performing the spinal puncture. The sensory block was tested with pinprick. Patients were called to answer questions regarding TNS. Prediction of the time course of sensory blockade was performed using a one-compartment PK model with absorption and a sigmoid PD model coded to dermatome level. Model estimation was performed using NONMEM (6.2) and PLT-Tools (2.0).

Results Inter-individual variability was large, with a sensory block level ranging from L5-C4, a median blockheight of T9, and a median onset of 13 minutes (1-87 min).

Posthoc individual prediction accuracy was good (SD 0.89 dermatomes) but population predictions were poor with a standard deviation in predicted blockheight of plus or minus 1.2 dermatome. None of the observed patient covariates were correlated to maximal achievable effect (PD model Emax). TNS was found in 10.8% of patients (95% CI 5-18%).

Conclusion The investigated patient covariates do not allow accurate prediction of sensory blockade in an individual before the initial dose has been given. reference 1. Krul-Sterk A., et al.Eur J of Anaesthesiol. 2009; 26: 82-83.

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Chronic neuropathic pain: structural changes in the superficial dorsal spinal cord R. Deumens R.J.P. Jaken M.A.E. Marcus E.A.J. Joosten Universitair Medisch Centrum Maastricht, Maastricht, the Netherlands

Introduction Chronic neuropathic pain (CNP) is common after neuropathy and refractory to treatment due to a limited understanding of the underlying mechanisms. Structural changes in the dorsal spinal cord have been proposed to relate to CNP following nerve injury. More specifically, noninjured nociceptive afferents were found to sprout in the superficial dorsal horn of denervated spinal segments. However, the specific termination pattern of these nociceptive afferents remains unclear. Therefore, we hypothesize that nociceptive

afferents sprout into a specific layer of the dorsal spinal cord, which is occupied with PKCγ+ interneurons normally receiving exclusively non-nociceptive inputs. This aberrant input may underlie CNP following L5 spinal nerve transection.

Methods Adult Sprague-Dawley rats received a L5 spinal nerve transection. Mechanical allodynia was assessed by measuring hind paw withdrawal threshold to tactile stimuli before and up to 21 days after injury. Immunohistochemical staining of PKCγ+ interneurons and sprouting primary afferents (GAP-43 immunoreactivity) was performed on several days following L5 spinal nerve transection.

Results Animals displayed mechanical allodynia of the ipsilateral, but not of the contralateral

hind paw up to 21 days post-injury. Immunohistochemical analysis at different survival times following L5 spinal nerve transection revealed an increased GAP-43 immunoreactivty in the ipsilateral dorsal horn compared to the contralateral dorsal horn. More specifically, sprouting in the PKC+ layer was more pronounced on the ipsilateral side compared to the contralateral side.

Conclusion We conclude that CNP after L5 spinal nerve transection is associated with sprouting of primary afferents. Moreover, sprouting occurred into regions normally not involved in nociceptive processing, which may underlie the CNP. However, the nature of these sprouting afferents needs further investigation to gain further knowledge, which may aid the development of novel therapies to more effectively treat CNP.


Spinal cord stimulation reduces the neuronal metabolism of the superficial dorsal horn (DH) after spinal cord stimulation (SCS) in rats with nerve injury induced pain. (preliminary data) H. Smits1 T. Pederzani2 J.L.M. Jongen2 E.A.J. Joosten1 F. Huygen2 1 Pain Management and Research Center, Anesthesiology department, Maastricht, the Netherlands 2 Erasmus MC, department of pain treatment, Rotterdam, the Netherlands

SCS is an established treatment for intractable neuropathic pain, especially Complex Regional Pain Syndrome type 1. The mechanisms of action of SCS are partially understood and more experimental research on this subject is needed. In the present study we performed an online in


vivo analysis of the mitochondrial metabolism of superficial dorsal horn neurons in neuropathic pain after spinal cord stimulation, using Autofluorescent Flavoprotein Imaging (AFI). Mitochondrial oxidized flavoproteins have the ability to absorb blue spectrum (435485 nm) photons. This leads to an immediate emission of green spectrum photons (520-590 nm), whose intensity (detected by a CCD camera) is a direct measure of neuronal metabolic activity. In a rat (n = 9) model of nerve injury induced pain, allodynia was induced and quantified using the von Frey test. 14 Days

post nerve injury the animals were anesthesized with urethrane and the spinal cord was exposed by a laminectomy at T13 (dura left intact).The animals were paralysed and mechanically ventilated and after 4 baseline AFI recordings, they received 30 minutes of SCS at T13 vertebral level (f 50 Hz, pulsewidth 0,2 ms, current 0,2 mA). After this, the AFI intensity was measured every 5 minutes for up to 65 minutes. A significant (P< 0.018) reduction in AFI intensity compared to baseline was measured 5 minutes after cessation of spinal cord stimulation, indicating a short reduction in superficial DH neuronal metabolism after SCS.

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Erythropoietin-like peptides protective role in neuropathic pain? A.M. Morariu M. Swartjes L.P.H.J. Aarts A. Dahan LUMC, Leiden, the Netherlands

Introduction Neuropathic pain (NP) is a debilitating condition, resistant to common therapeutic interventions, having often in etiology a partial peripheral nerve injury. Main symptoms are spontaneous pain, allodynia and hyperalgesia. Recent studies have revealed that erythropoietin (EPO), in addition to erythropoiesis, has key roles in acute/subacute biological responses to injury. EPO acts as a central player in the local downregulation of processes triggered by injury; it inhibits apoptosis and activates protective mechanisms; it reduces inflammation and local edema. Newly constructed peptides (ARA-290) mimic the external surface of EPO without primary sequence similarity. This peptide is demonstrated to recapitulate EPO’s tissue-protective, neurotrophic, and reparative properties, without having erythropoietic effects.

Methods The SNI model results in early (24 h), prolonged (>3months), and robust (all animals are responders) behavioral modifications of NP. The first ARA-290 dose (i.p.30µg/kg) was administered either 45 postoperative days (POD), 7POD, or 1POD, followed by other 4 administrations (i.p.30µg/kg every other 3days). The effect was measured with behavior pain tests.

Results ARA-290 was able to completely prevent the development of allodynia to mechanical/cold stimuli, and hypersensitivity to heat/mechanical stimuli when first administered at 1POD (no allodynia/hyper-

sensitivity in the first 18POD). When first administered at 7POD, ARA-290 was able to partially reverse the symptoms for 10±2 days. When first administered at 45POD, ARA-290 did not offer any relief in allodynia/hypersensitivity (Figure 1).

Conclusion Our observations indicate that the EPOlike peptide ARA-290 might be able to prevent the development of NP if administered early after the nerve trauma. These results might be supportive for a prophylactic treatment of patients undergoing orthopedic surgery, or immediately after traumatic nerve injuries, to minimize the risk of developing NP.

This study aims to investigate the effects of ARA-290 in a rat model of NP (Spared Nerve Injury - SNI model) and find the most effective protocol of intervention.

Caption 1. Tactile Allodynia


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Pulsed radiofrequency treatment for postmastectomy pain A. Lukas1 R.G.S.M. Perez2 1 NKI-AVL, Amsterdam, the Netherlands 2 VU Medical Center, Amsterdam, the Netherlands

Introduction Postmastectomy pain (PMPS) is a neuropathic pain syndrome predominantly caused by a lesion of the intercostobrachial nerve (IBN), resulting in pain located in axilla and ventral chest-wall. The present study was designed to evaluate the effect of pulsed radio frequency (PRF) on PMPS with IBN lesion.

Methods PMPS patients with IBN lesion who had undergone PRF treatment were identified retrospectively in the pain database

DOLORES©. PRF treatment had been performed at the thoracic nerves TH1 in patients with pain in the axilla, and TH6 in patients with ventral thoracic wall pain below the mamilla. Patients with pain at both localizations had received both PRF at TH1 and TH6. The PRF procedure was performed as described by van Zundert et al. [1] (PRF current 45 V/ 140 mA, pulses 2 Hz/20 ms, duration 6 min). Pre and post intervention pain-intensity NRS data were analyzed (Wilcoxon, p<0.05).

Results Between March 2006 and February 2009, 22 PRF treatments were identified in patients with PMPS, of which 11 in 9 patients with IBN lesion (mean age 52.8 (SD 10.8) years, mean duration PMPS 44.8 (SD 22.4) months). Six women had received PRF of

TH 1, and three of TH 1 and TH 6. A significant (p = 0.017) median pain reduction of 4 (IQR 1-5) was observed after TH 1 PRF, whereby 7 out of 9 patients experienced pain relief. For TH6 PRF, one patient experienced complete pain reduction (NRS change -4), and one patient experienced a slight increase (NRS change +1). For one patient only post intervention NRS was documented (NRS = 1).

Conclusion With all limitations of a retrospective analysis, PRF treatment of the thoracic nerves 1 and 6 seems to be an effective treatment option for PMPS with IBN lesion. reference 1.Van Zundert J, et al., Pain 2007, 127:173-182.


Chronic post-surgical pain: Is there a role for epidural anesthesia and analgesia in the prevention? H.M.S. Theunissen1 E.A.C. Bouman1 M.L. Peters2 H.F. Gramke1 M. van Kleef1 M.A.E. Marcus1 1 Maastricht Universitair Medisch Centrum (MUMC+), Maastricht, the Netherlands 2 Maastricht University, Maastricht, the Netherlands

Introduction Chronic post-surgical pain (CPSP) is a serious complication of surgery with a high impact on quality of life. Peripheral and central sensitisation are considered important mechanisms for developing CPSP. Therefore, we investigated if epidural analgesia, by blocking neuraxial input, could


be a tool in the prevention of CPSP after abdominal surgery.

Methods Based on a previously conducted cohortstudy, we studied changes in pain level 6 months after surgery, quality of life (SF36) and long-term recovery in patients receiving combined general and epidural anesthesia (n = 51) for abdominal surgery compared with general anesthesia (n = 50). Multivariate analysis was performed by logistic regression analysis.

Results 13.9% of the patients had chronic pain, 5 in the epidural group (10%), 9 in de general anesthesia group (18%). After adjustment for ASA, pre-operative pain, pain on day-

of-surgery, upper and lower abdominal surgery, the odds ratio for chronic pain in the epidural group was 0.88 (0.20 - 3.97). The SF-36 pain-score of the urology patients and the SF-36 pain-change-score were significantly better in the epidural group. There was no effect on the SF-36 total score. We found no differences with regard to long-term recovery except for the effect of surgery on memory or concentration.

Conclusion We could not demonstrate a preventive effect on the occurrence of chronic pain after abdominal surgery nor were there major differences with regard to long-term recovery.

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The inter-examiner reliability of pressure algometry for the region of sacroiliac joint K.M. Szadek S. Ustymenko S.A. Loer W.W.A. Zuurmond R.S.G.M. Perez VU Medical Center, Amsterdam, the Netherlands

Introduction The sacroiliac joint (SIJ) is a recognized source of low back pain. Despite a high prevalence (15-30%)1, SIJ pain can be difficult to diagnose. According to the IASP criteria, SIJ pain should be reproducible by provocation tests, but the tests are not specified 2. As pressure pain in the area of the SIJ is used to indicate SIJ pain, the present study was set up to evaluate the interexaminer reliability of pressure algometry in the region of the SIJ using the Wagner Force Dial dynamometer.

caudal from the posterior superior iliac spine, and 4 more 2cm laterally, cranially, medially and caudally from the first point. Starting with the right side, the examiner applied a constant pressure on each point until the subject reported pain. After 5 minutes, the measurements were repeated by a second examiner. The inter-examiner reliability was tested with the Interclass Correlation Coefficient (0=no reliability, 1=perfect reliability).

Results Mean applied pressure was 8.5 (SD 2.8) on the right side and 8.3 (SD 2.8) on the left side (female: right 7.0 (SD 2.5), left 7.2(SD

2.5); men right 9.7 (SD 2.6), left 9.3 (SD 2.7). The reliability for each measured point varied between ICC 0.66-0.83 (see table 1). The mean reliability for the right side was ICC 0.8 (95% CI 0.64-0.9) and the left side ICC 0.83 (95%CI 0.7-0.9).

Conclusion Manual algometry for the SIJ region, with the Wagner Force Dial dynamometer appeared to be reliable in healthy volunteers. references 1. Schwarzer A.C. et al. Spine: 1995;20(1):31-37. 2. Merskey H. & Bogduk N. Classification of chronic pain. IASP 1994.

Methods Forty one healthy volunteers were included: 19 women and 22 men, mean age of 36 years (SD 11). Five measure points in the right and left SIJ region were marked on the skin of each subject: 1cm medial and

Caption 1: Table 1. Reliability for measured points


Anti-inflammatory treatment for Complex Regional Pain Syndrome type-1 (CRPS-1): a meta-analysis S.G.L. Fischer R.S.G.M. Perez S.A. Loer W.W.A. Zuurmond

analysis, effects of anti-inflammatory interventions were evaluated, with pain, motor function and clinical improvement or the development of CRPS as outcome measurements.

VU Medical Center, Amsterdam, the Netherlands

Embase, Cochrane, Medline and Pubmed databases were consulted from the start of these databases up to October 2008 for studies evaluating anti-inflammatory therapy for CRPS-1 or its synonyms. The studies were rated according to methodological strength using the Delphi list. Hedges’s G

CRPS-1 is characterized by pain, swelling, temperature and colour changes of the affected extremity. The pathophysiological mechanism is not fully understood, but an inflammatory process plays a role in this disease. In this meta-


effect sizes (ES) or odds ratio’s (OR) were calculated for articles of high methodological quality. Analysis was performed for different groups of medication and outcome measurements. Twelve studies of high methodological strength and eleven studies of low methodological strength were found meeting the inclusion criteria. Treatment with oral corticosteroids shows effect on pain, with a pooled ES of 25.45. It is also likely that

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abstracts 2009 corticosteroids have positive effects on clinical improvement with a pooled ES of 28.56. Contradictory results were found for effects on motor function. Scavengers show no effect on pain, but it is likely that there are effects on clinical improvement, whereby an ES of 11.00 was found. Indications are found for better outcome of motor function after treatment with dymethylsulfox-

ide (OR 0.12, p=0.006). Evidence was found for the effect of vitamin C on prevention with an OR of 0.25 (p=0.0004). This meta-analysis provides positive findings for effects of anti-inflammatory treatment on CRPS-1. Most favourable effects were found for prevention with scavengers, but treatment of pain with corticosteroids

shows promising results as well. Large high quality trials with more homogeneous study populations are needed to obtain information on the effect of different therapies on main symptoms of the individual patient.


Role for toll like receptor-4 in ventilatorinduced diaphragm dysfunction in mice W.J.M. Schellekens UMC St. Radboud, Nijmegen, the Netherlands

Introduction Mechanical ventilation is associated with diaphragm dysfunction and systemic inflammation. Whether inflammation is involved in the development of ventilator-induced diaphragm dysfunction is unknown. Toll like receptor-4 (TLR-4) is known to activate intracellular inflammatory pathways. Aim: To investigate the role of TLR-4 signaling in the development of ventilatorinduced diaphragm dysfunction.

Methods Wild-type (WT, n=8) and TLR-4 knock-out (TLR4-KO, n=7) mice were mechanically ventilated for 8 hours (tidal volume 8 ml/

kg; PEEP 1,5 cm H2O; respiratory rate 170/min). Immediately after sacrifice diaphragm muscle bundles were dissected. From these bundles chemically skinned fibers were isolated. Absolute maximal force generation was determined upon calcium activation (pCa 4.5) (n=8 per group). mIL1a, mIL-1b, mIL-6, TNF-a and mKC were analyzed by ELISA in lung- and diaphragm homogenates (n=6 cWT cKO; n=8 vWT; n=7 vKO).

Results Pao2 / Fio2 ratio were not significantly different between WT and TLR4-KO mice after 8 hours of mechanical ventilation (492 ± 40 and 531 ± 45 respectively). Absolute maximal force generation of diaphragm fibers from TLR4 KO mice was 15% higher compared to WT mice (2,34 ± 0.32 mg

vs. 2,04 ± 0.13 mg respectively). Levels of mIl-1 b in lung and mIL-6 and mKC in diaphragm and lung were significantly increased in WT mice after 8 hours of mechanical ventilation compared to TLR4KO, but not mIL-1a, mIl-1b and TNF-a in diaphragm and mIL-1a and TNF-a in lung.

Conclusions 1. TLR-4 signaling is involved in the development of the inflammatory response in diaphragm and lung following mechanical ventilation. 2. TLR-4 signaling does not affect pulmonary function in mechanically ventilated mice.


Measurement of perioperative changes in the pulse pressure variation in spontaneously breathing patients T.A. van Veelen D.C. Hooijberg K. Treskes D.P. Veerman C. Boer VU Medical Center, Amsterdam, the Netherlands

Pulse pressure variation (PPV) is an extensively studied dynamic index for the prediction of volume responsiveness in ventilated patients.


We recently showed that PPV as measured by a non-invasive continuous blood pressure measurement device during controlled breathing and autonomic function testing may also be representative for fluid shifts in spontaneously breathing volunteers. We here investigated whether our approach additionally enables the detection of changes in the PPV after anesthesia and surgery in spontaneously breathing patients.

PPV was determined in surgical patients using a non-invasive continuous finger blood pressure measurement device (Nexfin HD®; BMEYE, Amsterdam). Exclusion criteria were a BMI <15 or > 35 and pre-existing co-morbidities. Measurements were performed before surgery and 3 subsequent days postoperatively. After baseline measurements during supine steady state, patients executed controlled breathing (10 breaths / minute) and a Valsalva maneuver

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to determine PPV. Data was analyzed using a t-test for paired observations. The PPV during controlled breathing as measured in 19 patients (4 males/15 females; 45±10 years; BMI 26.2±4.1 m2/kg) showed a slight variation over 4 consecutive days in the perioperative period. The PPV on day 1 postoperatively dropped from 10.4±4.5% to 7.4±2.6% (P=0.025) and returned to

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changed in the perioperative period due to the limited impact of controlled breathing on intrathoracic pressure-provoked fluid shifts. However, our results support further development and validation of this method as clinical measure for fluid responsiveness in spontaneously breathing patients.


Remifentanil-propofol interaction on spontaneous respiration in healthy volunteers tested under open-loop conditions M.C.A. Boom E. Olofsen D. Nieuwenhuijs L. Teppema A. Dahan LUMC, Leiden, the Netherlands

Introduction Opioids and propofol are used increasingly during diagnostic procedures. Few studies have addressed the effect of these drugs on the control of breathing. In the current study we assessed the effect of remifentanil awake and asleep (by propofol) on spontaneous breathing in healthy volunteers.

Methods Ten male volunteers participated in the protocol after approval by the local ethics committee. Each subject performed two runs: (I) remifentanil, (II) remifentanil + propofol (1000 ng/ml TCI). The remifen


tanil infusion schemes varied between subjects from fast to slow (target concentration 3 - 4 ng/ml) The ventilation (Vi) data were analyzed with a mathematical model of the ventilatory control systems consisting of two parts. One part: (1) Vi = G*(PCO2 - B) and B = B’*(1 + A100*Ce), and another part: (2) Vi = VAB*(1-A100*Ce), where Ce is effect-site remifentail concentration, G gain of the central controller, B apneic threshold and A100 = 1/C100. C100 is the concentration remifentanil causing a doubling of B (eqn. 1) or the concentration causing apnea (eqn. 2). Note that eqn. (1) assumes an active controller, while eqn. (2) assumes no active controller. Parameter L is introduced to weigh which of the two

mechanisms is involved in the development of respiratory depression.

Results Run I: C100 effect on B = 6.1 ng/ml; G = 3.5 L.min-1.kPa-1; L = 1. Run II: C100 effect on Vi = 2.7 ng/ml; G = 1.4 L.min-1.kPa-1 and L = 0.8. No apnea was observed after just remifentanil (run I), while apnea was observed in all remifentanil exposures on top of low-dose propofol (run II). This latter effect was independent of the speed of remifentanil infusion.

Discussion These data indicate a differential effect of remifentanil awake versus remifentanil asleep (i.e., propofol-induced sleep) with a synergistic effect of sleep on opioidinduced respiratory depression.

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Renal microvascular endothelial activation in a mouse model of hemorrhagic shock: is the neutrophil a key player in organ dysfunction? F.M. Wulfert M. van Meurs N.F. Kurniati R.M. Jongman J.G. Zijlstra M.M.R. Struys G. Molema UMCG, Groningen, the Netherlands

Introduction Acute kidney injury (AKI) is a complication of hemorrhagic shock. Interaction between activated neutrophils and endothelial cells is considered to play a prominent role in the pathophysiology of AKI. We hypothesized that, in the kidney, hemorrhagic shock (HS) rapidly activates microvascular endothelial cells toward a pro-inflammatory status which is due to neutrophil -endothelial cell interaction. Thus depletion of neutrophils would prevent endothelial

activation, thereby diminishing the inflammatory response, and ultimately attenuating the development of AKI.

Methods For induction of HS, anesthetized male C57Bl/6 mice were subjected to controlled HS with a MAP of 30 mmHg during 90 minutes followed by resuscitation with 6% hydroxyethyl starch. After 90 min of hemorrhagic shock and 1, 8, or 24 hours post volume resuscitation mice were sacrificed. In selected animals, neutrophil depletion was established by intraperitoneal injection of anti-NIMP antibody 24 hour prior to HS versus IgG control. mRNA expression of P-selectin, E-selectin, VCAM-1, and ICAM-1 was measured in kidney by real time RTPCR. Renal localization of selected proteins was determined with immunohistochemistry. Micro-albuminuria was measured in mouse urine as a marker of kidney function.

Results Neutrophil depletion led to upregulation of adhesion molecules compared to control mice. In the early shock period neutrophil depleted mice showed significantly less expression of P-, E-selectin, VCAM-1, and ICAM-1 than their IgG-treated controls. However, after resuscitation no significant difference between neutrophil depleted and neutrophil competent mice was observed. Shock induced albuminuria was not reversed by leukocyte depletion.

Conclusion Neutrophil depletion attenuated the induction of endothelial adhesion molecules during the early hemorrhagic shock period, no differences were seen after resuscitation. In our model, deterioration of kidney function was not influenced by neutrophilendothelial interaction after hemorrhagic shock and resuscitation.


Evaluation of different blood drawing tech niques on the results of platelet function tests F.H. Tijssen Y.M.C. Henskens H.M.S. Theunissen R. van Oerle K. Hamulyak H. ten Cate M.A.E. Marcus M.D. Lance MUMC+, Maastricht, the Netherlands

Introduction Pre-analytic variables can influence results of laboratory tests. Whole blood tests for platelet function can be used as point of care (POC) tests in operating rooms. In patients undergoing (cardiac) surgery, blood can be drawn from different collection sites using different needles or canules.


The aim of this study is to examine whether the site or technique of blood drawing has an effect on the results of two POC platelet functions tests (Multiplate ‘ and PFA-100).

Methods After institutional approval 11 patients scheduled for elective cardiac surgery gave written informed consent. We collected blood at four different sites: 16G venous canula, 18G arterial line, 9F central venous line and venipuncture (18G needle). Blood was aspirated in a syringe and three sampling tubes (one 3,2 % citrate tube, one EDTA tube and one hirudin tube) were directly filled. All whole blood samples were analyzed for Hb and Plt count, with an impedance aggregometer (MultiplateTM analyzer, agonists: ASPI/ADP/Coll/RISTO/

TRAP) and the Platelet Function Analyzer (PFA-100 agonist: collagen/epinephrine, collagen/ADP). Results were analysed using Friedman’s ANOVA and Wilcoxon tests with Bonferroni correction.

Results All patients had normal Hb and platelet counts at the time of the first collection. There were no significant differences between the four collection sites for all parameters measured by impedance aggregation or platelet function analyzer.

Conclusion This study shows that the blood drawing techniques specified above can be equally used when these tests are applied in clinical studies.

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Perioperative alterations in the stress imprint in human plasma lead to the induction of proapoptotic and stress markers in cardiomyocytes K.W.L. van Deutekom J.R. de Jong J.W.A. Romijn H.W.M. Niessen C. Boer VU Medical Center, Amsterdam, the Netherlands

Cardiopulmonary bypass (CPB) is known for its induction of systemic inflammation and stress pathways, both playing a central role in postoperative complications. This systemic stress condition may additionally affect cardiomyocyte function in the postoperative phase, but this is difficult to study in patients. We therefore designed a cellular read-out model which allows a time-dependent analysis of the human blood stress imprint on cardiomyocyte stress and apoptosis signaling using plasma from patients undergoing cardiothoracic surgery with CPB.

To investigate the effects of CPB-induced systemic stress on cardiomyocytes, H9C2 rat cardiomyocytes were stimulated with plasma samples of patients undergoing Coronary Artery Bypass Grafting (CABG). Samples were drawn before and after CPB. Stimulated cardiomyocytes were analyzed for the activation of inflammation-related stress markers using Western blot analysis, i.e., p38 and Akt. Results are expressed in arbitrary units. Stimulation of cardiomyocytes with human plasma for 1 and 4 hours resulted in a 7-fold sustained increase of p-p38 expression as compared to baseline. Akt expression initially reduced from 0.45 A.U. to 0.1 A.U. after 1 hour of exposure, but this effect was transient and after 4 hours Akt expression increased above baseline values.

Cardiopulmonary bypass alters plasma parameters that induce intracellular signal transduction pathways related to stress and apoptosis. This is exemplified by increased expression of activated p38 and reduced expression of activated Akt. Moreover, we here demonstrate a novel read-out model that allows the analysis of the impact of the human plasma stress imprint on intracellular signaling in cardiomyocytes. Our results may increase insight in signal transduction pathways that are involved in postoperative cardiac deterioration in surgical patients.


Cardiac Output monitoring in cardiac surgery: invasive versus non-invasive T.A.J. Lohuis N. Tajaate N.A.H. Helgers H.M.S. Theunissen M.A.E. Marcus M.D. Lance MUMC+, Maastricht, the Netherlands

Introduction Accurate and reliable noninvasive cardiac output and index measurement could be a valuable adjunct in clinical management. Especially because our population is aging and cardiac morbidity becomes more challenging. A recent advance in bioimpedance technology (velocimetry) promises a more precise and stable measurement using only four conventional ECG-electrodes. We compared this method to the golden standard (pulmonary artery catheter).


Methods We randomly included 22 patients out of our cardiac surgery population. They were anaesthetised according local standards. All received a pulmonary artery catheter, were connected to continuous cardiac output monitoring (CCO-Vigilance-Edwards) and to electrical velocitymeter monitoring (Aesculon®-Osypka Medizintechnik Germany) the way as recommended by the manufacterer. There were 8 measurements per patient (T1 before incision, T2 before cannulation, T3a on extracorporal circulation (ECC), T3b after Protamineinjection, T4 after ECC, T5 30 min on ICU, T6 60 min after detubation, T7 morning after cardiac surgery).

Results Difference in measurement T3b, T4 and T5 were significant (table).

Caption 1: Table

We detected no significant difference between cardiac output measurement on the Aesculon® and EEC-flow, T3a (p=0.087). The responsiveness of the CI-measurements at different times is good (figure). All measurements diverged at the upper limit of CI>3. We have no data of patients with very low CI.

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abstracts 2009 Conclusions In stabile conditions, ventilated or spontaneous breathing (T1, 2, 6 and 7), we found no difference between both methods. At higher CI (> 3) measurements are less reliable. The Aesculon®monitor appears to produce reliable data when using ECC, more studies will be necessary.

Caption 2: figure


Thrombomodulins lectin like domain (LeD) alters outcome and inflammation in a murine CLP mouse model T. Harendza1 T. Barkhausen2 F. Echtermeyer2 G. Theilmeier1 Medizinische Hochschule Hannover, Hannover, Germany 1 Department of Anaesthesiology and Intensive Care Medicine, Experimental Anaesthesiology, Hannover Medical School, Germany 2 Department of Trauma Surgery; Experimental Trauma Surgery, Hannover Medical School, Germany

Introduction Sepsis-induced acute lung failure remains tough to treat because the underlying mechanisms are poorly understood. We demonstrated that lack of thromodulins lectin-like domain (LeD) in mice causes a proinflammatory phenotype and augmented inflammatory response to inflammatory stimuli. We therefore examined the role of TMLeD during development of septic lung failure.


Methods Sepsis was triggered in LeD deficient (TMLeD/LeD )- and wild-type (WT) mice by caecal ligation and puncture (CLP). 4-day survival was recorded. Arterial blood gas analysis, BALF and cytospin studies were performed. Lung tissue was snap frozen after 12h and after 96h for rtPCR or paraffin embedded for histological exploration.

Results Four days after CLP 20% of WT- and 50% of LeD-/--mice died (n=20). 12h after intervention, both CLP groups were in a state of compensated acidosis (TMLeD/ LeD :7,08±0,06 vs. WT:7,21±0,06,n=21, p>0,05), with lowered HCO3akt. (10,9±1,3 vs.13,6±1,0,n=21,p<0,05), BE (-18,1±2,3 vs.-13,2±0,9 mmol/l,n=21, p>0,05), sO2- (82,6±4,8 vs. 97,8±1,1, n=21, p<0,05) and pO2-levels (79,4±6,4 vs. 130,9±6,6,n=21,p<0,05). RTPCR revealed a more than 2-fold increase in ICAM-1

expression in TMLeD/LeD -mice compared to the WT-group (12h TMLeD/LeD :2,4±2,4; 96h TMLeD/LeD :2,2±0,8), generating elevated macrophages in BALF and lung after 12h (BALF:79,7±4,6 vs. 43,3±5,7 /100cells, n=23, p<0,05; Lung:21,9±2,9% vs. 18,7±3,6%,n=95, p>0,05).

Conclusion TMLeD/LeD have enhanced macrophage recruitment and activation accompanied by impairments in gas exchange, acidbase-balance and elevated lethality. These effects could be due to increased ICAM-1 expression. In summary, therapeutically the lectin-like domain could improve outcome of sepsis-induced lung failure and we will proceed to evaluate this molecules clinical usefulness.

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The impact of surgery on nitric oxide and its associated cytokine and amino acid biochemical pathways J.W.H. Hol D.F. Fekkes C Heijmas-Antonissen F. Zijlstra M. Klimek R.J. Stolker Erasmus MC, Rotterdam, the Netherlands

Introduction The plasma amino acid profile of patients undergoing surgery shows promise for monitoring physiological stress during the peri-operative period (1). Plasma cytokine levels are an accepted method of monitoring peri-operative inflammation (2). Cytokines and amino acids regulate nitric oxide levels by activating inducible nitric oxide synthase, endothelial nitric oxide synthase and substrate availability. Therefore, the peri-operative process provides a good opportunity to learn

Caption 1. Figure 1: Plasma nitric oxide levels


more about the effects of amino acids and cytokines on nitric oxide metabolism. A physiological level of nitric oxide is important for maintaining appropriate vascular tone and related organ perfusion. High pathological levels of NO cause a systemic inflammatory response syndrome (SIRS) while too little NO cause’s organ ischemia. Arginine is the amino acid precursor for nitric oxide and ornithine, an amino acid used for wound healing.

Results

Methods

Conclusion

We measured plasma levels of NO, arginine, ornithine, IL-6, IL-8 and IL-10 during five peri-operative time points before, during and after surgery in a prospective, two-armed observational study involving 28 female patients undergoing abdominal hysterectomy and vulvectomy operations.

The heavy surgery group consumes more ornithine; this is likely due to increased wound healing. The IL-6 peak did not cause pathological NO production via iNOS, proper hemodynamic control might be an explanation. Our data suggests that good peri-operative care is important in order to preserve physiological NO metabolism.

The laparotomy group produced a significant IL-6 peak at the end of the operation. The vulvectomy group was found to have significantly more nitric oxide at 24 hours and 96 hours post operative (Fig. 1). Throughout the experiment arginine levels did not differ significantly between experimental groups, while significantly less plasma ornithine was found post operative in the laparotomy group (Figure 2).

Caption 2. Figure 2: Plasma ornithine levels

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High prevalence of lifestyle risk factors in the surgical population N.H.A. Lecluse1 R.L.O. v.d. Laar1 J.P. Hering2 C. Boer1 1 VU Medical Center, Amsterdam, the Netherlands 2 Westfriesgasthuis, Hoorn, the Netherlands

Introduction The Dutch surgical patient population is increasingly dominated by patients with acquired health risk factors. The presence of two or more so-called lifestyle risk factors is clearly associated with the development of comorbidities and may even be related to the development of perioperative complications. Until now, the exact prevalence of lifestyle risk factors in the surgical population is unknown. The aim of this study was therefore to determine

the prevalence of lifestyle risk factors in the surgical population in our hospital.

Methods The medical files of patients of 18-75 years old who visited the preoperative outpatient clinic of the VU University Medical Center in 2008 were retrospectively evaluated. The following lifestyle risk factors were evaluated: obesity (BMI > 25 kg/m2), hypertension (systolic BP > 140 or diastolic BP > 90), smoking (yes or no), diabetes (yes or no), physical condition and a history of heart disease.

Results 4.808 adult patients visited the preoperative outpatient clinic, of which 45.8% possessed two or more lifestyle risk factors, independent of gender. Although the

prevalence of lifestyle risk factors increased with age, 27% of the patients < 45 years possessed two or more lifestyle risk factors. Obesity and hypertension appeared to be the lifestyle risk factors with the highest prevalence, whereas a BMI > 30 kg/m2 doubled the risk of having two or more lifestyle risk factors.

Conclusion The prevalence of lifestyle risk factors in the surgical population is high, and this phenomenon is silently accepted by anesthesiologists. However, the necessity of anesthesia and surgery may provide a golden opportunity to improve preoperative patient health, thereby reducing the chance for perioperative and postoperative complications.


Prehospital endotracheal intubation does not associate with outcome in patients with severe traumatic brain injury G. Franschman1 S.M. Peerdeman1 T.M.J.C. Andriessen2 S. Greuters1 G.N. Jukema1 S.A. Loer1 C. Boer1 1 VU Medical Center, Amsterdam, the Netherlands 2 Radboud Universiteit Nijmegen, Nijmegen, the Netherlands

The prognosis of patients with severe traumatic brain injury (TBI) with a GCS ≤ 8 relies on suitable support of respiratory function. Adequate prehospital respiratory management is strongly associated with improved outcome in these patients. Here we investigated whether endotracheal intubation is an independent predictor of outcome in TBI patients in addition to classical prognostic parameters in the prehospital period.


Medical files of 340 TBI patients with a GCS ≤ 8 who were admitted to the ER of two level 1 trauma centers were analyzed in a retrospective fashion. Patients aged 44 ± 21 years and were typically male (70%). The median ISS estimated 29 and 70% of all patients were intubated in the prehospital phase. Actual and predicted (CRASH score) mortality approximated 43% and 50%, respectively. Of all survivors (n =149), only 38 patients made a good recovery. Mortality was strongly associated with increased age, the prehospital incidence of hypotension and a disturbed pupil reflex, but not with hypoxia, GCS value, CT score or presence of a tube. Moreover, posttraumatic development of disabilities in survivors was significantly associated with age, disturbed pupil reflex at trauma scene and severity of brain lesions detected by

CT analysis in the first hour after hospital admission. Neither intubation nor hypoxia is an independent outcome predictor in our severe brain injury population. Our data show that pupil reflex, age and incidence of hypotension are predictors of mortality in TBI patients with GCS≤8 , whereas worse CT classification is associated with an unfavorable outcome in TBI survivors. Our results warrant for a prospective investigation of the role of intubation in the outcome of TBI patients.

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The effects of implementing a new schedule at the preoperative assessment clinic G.M. Edward B. Preckel B.S. Martijn F.J. Oort J.C.J.M. De Haes M.W. Hollmann AMC, Amsterdam, the Netherlands

Introduction Long waiting times are a problem often encountered at the preoperative assessment clinic (PAC). To tackle this problem, we redesigned our appointment system using a multi-factor approach. Waiting times and patients’experiences before and after implementation of the new appointment system were compared.

Methods During three weeks, patient flow times were measured at the PAC. These were used to calculate the procedure time of the nurse and physician, and the patient’s waiting time. Patients who visited the PAC received the Patient Experiences with the Preoperative Assessment Clinic (PEPAC) questionnaire to measure their experiences. Waiting times and patients’ experiences before and after implementation of the new appointment system were compared.

Results By making the reserved consultation time dependent on patients’ estimated ASA physical status, mean total waiting time was reduced from 26 (SD 23) min to 16 (15)

min (P<0.001). Thirty percent of the patients were late for their appointment. On average physicians were 21 (10) min late for their first appointment. The questionnaire was sent to 476 patients (response 68%). On a 0-100 scale, patients’ experiences with waiting improved from 49 (19) to 52 (18) and patients’ mean overall appraisal of the PAC increased from 78 (16) to 81 (14) (P<0.05).

Conclusion The new appointment system reduced the waiting time at the PAC and patient experiences were more positive after implementation of the new system. All efforts should be made to avoid unpunctuality from physicians and patients.


Pulse transit time during induction by a propofol bolus V. Rezvani M. Reekers F. Boer A. Dahan J. Vuyk

The aim of this study was to determine whether PTT can be used as an indicator of depth of anesthesia in ASA I+II patients during the induction of general anesthesia by a propofol bolus.

LUMC, Leiden, the Netherlands

Methods

Background

12 adult ASA I+II patients scheduled for elective surgery were included.

Pulse transit time (PTT) is the time needed by a pulse wave to travel between two arterial sites. PTT can be measured by calculating the time interval between the R wave on the ECG and the pulse in the finger measured by photoplethysmography. PTT and blood pressure are inversely related. PTT lengthens when blood pressure falls due to a decrease in vascular tone after injection of anaesthetics like propofol.


PTT was measured as the interval between the peak of the R-wave on the ECG and the pulse in the finger pad measured by plethysmography. During the experiment depth of anesthesia was measured by BIS with moving average over 15 seconds. Patients received an induction bolus dose of propofol 3 mg/kg (n=2) or 2 mg/kg (n=10). After BIS returned to 70 or patients showed signs of arousal, the experiment ended.

Results PTT rapidly increased after induction by a propofol bolus. PTT was still equally prolonged while propofol concentration and BIS had almost returned to baseline level. The elevation of PTT occurred faster than BIS depression.

Conclusion This study shows that PTT increases rapidly after induction of anesthesia by a propofol bolus in ASA I/II patients. The increase in PTT was equal among all patients and occurred earlier than BIS depression. Regaining of consciousness towards a lighter level of anesthesia is not accompanied by returning of PTT to baseline level. PTT might be a useful tool in assessing the induction level of anesthesia due its fast change compared to BIS.

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Application of microarray-based gene expression technology to malignant hyperthermia M.S. Snoeck1 J.C.F. Koenen1 E. Sterrenburg2 S. van der Maarel2 1 Canisius-Wilhelmina Ziekenhuis, Nijmegen, the Netherlands 2 Center for Human and Clinical Genetics LUMC, Leiden, the Netherlands

Introduction DNA microarray technology can be used to monitor the expression levels of thousands of different genes simultaneously. To study the muscle contracture mechanism of malignant hyperthermia susceptible patients upon halothane stimulation, we performed microarray gene expression analysis on both unstimulated and halothane stimulated muscle samples.

Methods Quadriceps muscle biopsies were taken from 6 patients who were tested for susceptibility to MH using the IVCT. Of each person, 1 muscle sample was immediately frozen in liquid nitrogen at removal on


the OR and the other sample was frozen in liquid nitrogen at completion (3% v/v) of the halothane-IVCT that had turned out positive. Total RNA was isolated and hybridized to Illumina Mouse Sentrix-6 BeadChips 1.

Results ANOVA statistical analysis of the microarray data revealed 79 genes differentially expressed (p<0.001, Bonferroni corrected). 28 were downregulated and 51 were upregulated. Annotation of the genes with the Webgestalt software enabled the different genes to be classified according to function 2. The table shows a summary of the functional groups which are overrepresented in

MH patients upon stimulation with halothane. Striking is that the genes in these functional groups are mainly upregulated.

Conclusion Looking at the results, it seems that the MAPK signaling pathway is activated upon halothane stimulation. Downstream, this can lead to activation of transcripton factors, a group that is also functionally overrepresented. references 1. Turk et al, 2004. BMC. Genomics 5:57. 2. Zhang et al, 2005. Nucleic Acids Res. 33: W741-W748.

Functional group overrepresented

number of genes

p-value

MAPK signaling pathway

7

3.25E-05

Map kinase phosphatase activity

2

9.50E-04

Transcription factor activity

8

2.94E-03

Apoptosis

7

7.52E-03

Negative regulation of cellular physiological process

8

5.53E-03

Response to che mical stimulus

6

4.29E-03

09-09-09 11:01

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Refs. 1 Fricke JR, Hewitt DJ, Jordan DM, Fisher A, Rosenthal NR. A double-blind placebocontrolled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain. Pain 2004; 109: 250-257. 2 Medve RA, Wang J, Karim R. Tramadol and acetaminophen tablets for dental pain. Anesth Progr. 2001; 48(3): 79-81. 3 Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data metaanalysis of single-dose oral tramadol plus acetamino-phen in acute postoperative pain. J Pain Symptom Manage. 2002; 23(2):121-130. 4 Lanas A et al. Risk of upper gastrointestinal bleeding associated with non-aspirin cardiovascular drugs, analgesics and nonsteroidal antiinflammatory drugs. European Journal of Gastroenterology & Hepatology; 2003; 15; 173-178. 5 Whelton A. Renal and Related Cardiovascular Effects of Conventional and COX-2-Specific NSAIDs and Non-NSAID Analgesics. American Journal of Therapeutics; 2000; 7; 63-74.6 Radbruch L, Grond S, Lehmann KA. A Risk-Benefit Assessment of Tramadol in the Management of Pain. Drug Safety 1996, Jul; 15(1): 8-29. 7 Grond S, Sablotzki A. Clinical Pharmacology of Tramadol. Clin Pharmacokinet 2004; 43 (13): 879-923. Samenstelling: ZALDIAR filmomhulde tabletten Productinformatie Zaldiar® 37,5 mg/325 mg bevatten 37,5 mg tramadol en 325 mg paracetamol. Indicaties: is bestemd voor de symptomatische behandeling matige Samenstelling: ZALDIARZALDIAR filmomhulde tabletten bevatten 325 mg paracetamol envan 37,5 mg tot ernstigeIndicaties: pijn. Dosering: Het wordt aanbevolen te starten met twee tabletten, tramadol. ZALDIAR is bestemd voor de de behandeling symptomatische behandeling van matige maximale dosering per dag is acht tabletten (overeenkomend met 300 mg tramadol en 2600 mg tot ernstige pijn. Dosering: het wordt aanbevolen de behandeling te starten met twee tabletparacetamol). bij kinderen jonger dan 12met jaar. 300 Contra-indicaties: ten, maximaleZALDIAR doseringwordt per niet dag aanbevolen is acht tabletten (overeenkomend mg tramadol Overgevoeligheid voor tramadol, paracetamol vooraanbevolen één van de bij hulpstoffen. met en 2600 mg paracetamol). ZALDIAR wordtofniet kinderen Acute jonger intoxicatie dan 12 jaar. alcohol, hypnotica, centraal werkendevoor analgetica, opioïden of psychotrope middelen. Gebruik van Contra-indicaties: overgevoeligheid tramadol, paracetamol of voor één van de hulpstoffen. MAO-remmers, leverfunctiestoornissen, dieanalgetica, niet onderopioïden controleofispsychotrope door middel Acute intoxicatieernstige met alcohol, hypnotica, centraalepilepsie werkende van behandeling. waarschuwingen: wordt niet aanbevolen bij die patiënten met middelen. GebruikSpeciale van MAO-remmers, ernstigeZALDIAR leverfunctiestoornissen, epilepsie niet onder ernstige (creatinineklaring < 10 ml/min) of bijZALDIAR ernstige wordt ademhalingsinsufficiënte. controle nierinsufficiëntie is door middel van behandeling. Waarschuwingen: niet aanbevolen bij Niet gelijktijdig gebruiken met andere paracetamol of tramadol bevattende patiënten met ernstige nierinsufficiëntie (creatinineklaring < 10 ml/min) of bij geneesmiddelen ernstige ademhalingsinsufficiëntie. gelijktijdig gebruiken met andere paracetamol tramadol bevattende zonder een arts te Niet raadplegen. Epilepsiepatiënten die met behandelingofonder controle zijn of geneesmiddelen zonder een raadplegen. Epilepsiepatiënten die met behandeling onder patiënten die ontvankelijk zijnarts voorte aanvallen, mogen alleen met ZALDIAR worden behandeld controle zijn of patiënten die ontvankelijk zijngebruik voor aanvallen, mogen alleen met ZALDIAR worden als dat absoluut noodzakelijk is. Gelijktijdig van opioïd-agonisten-antagonisten (nalbufine, behandeld als pentazocine) dat absoluutwordt noodzakelijk is. Gelijktijdig vanvoorzichtigheid opioïd-agonisten-antagonisten buprenorfine, afgeraden. ZALDIAR gebruik moet met worden gebruikt (nalbufine, buprenorfine, pentazocine) wordt afgeraden. metmet voorzichtigheid bij opioïd-afhankelijke patiënten of bij patiënten met eenZALDIAR craniaal moet trauma, een aanleg worvoor den gebruiktaandoeningen, bij opioïd-afhankelijke patiënten of bijinpatiënten met van een shock, craniaal met een convulsieve galwegaandoeningen, een toestand in trauma, een toestand van aanleg voor convulsieve aandoeningen, galwegaandoeningen, in een toestand van shock, in een veranderd bewustzijn van onbekende oorzaak, met problemen van het ademhalingscentrum of toestand van veranderd bewustzijn onbekende oorzaak, met problemen van het ademhalingsde ademhalingsfunctie, of met eenvan verhoogde intracraniale druk. Interacties: MAO-remmers, centrum of de ademhalingsfunctie, of met een verhoogde opioïd-agonisten-antagonisten, intracraniale druk. Interacties:SSRI’s, MAOalcohol, carbamazepine en andere enzyminductoren, remmers, andere alcohol,opioïdderivaten, carbamazepinebenzodiazepinen, en andere enzyminductoren, opioïd-agonisten-antagonisten, triptanen, barbituraten, anxiolytica, hypnotica, sedatieve SSRI’s, triptanen,sedatieve andere opioïdderivaten, barbituraten, anxiolytica, hypnotica, antidepressiva, antihistaminica,benzodiazepinen, neuroleptica, centraal werkende antihypertensieve sedatieve antidepressiva, sedatieve antihistaminica, centraal werkende middelen, thalidomide, baclofen, warfarines, andere neuroleptica, geneesmiddelen waarvan bekendantihyperis dat ze tensieve middelen, thalidomide, baclofen, warfarines, andere geneesmiddelen waarvan bekend CYP3A4 remmen, bupropion. Meest voorkomende bijwerkingen: misselijkheid, duizeligheid en is dat ze CYP3A4 remmen, Meest voorkomende bijwerkingen: misselijkheid, slaperigheid, hoofdpijn, beven, bupropion. verwardheid, stemmingswisselingen, slaapstoornissen, braken, duizeligheden,droge slaperigheid, beven, verwardheid, stemmingswisselingen, slaapstoornisconstipatie, mond, hoofdpijn, diarree, abdominale pijn, dyspepsie, flatulentie, zweten, pruritus. sen, braken, constipatie, droge mond, diarree, pijn,per dyspepsie, flatulentie, Houdbaarheid: 3 jaar. Verpakking en prijs: 30 abdominale of 60 tabletten verpakking. Prijs: ziezweten, Z-Index pruritus. Houdbaarheid: 3 jaar. en prijs: 30 ofUR. 60 tabletten per verpakking. Prijs: taxe. Registratienummer: RVGVerpakking 28113. Afleverstatus: Vergoeding: volledig vergoed. zie taxe. Afleverstatus: UR. Vergoeding: volledig vergoed. Datering IB tekst: april 2006. Datering IB tekst: April 2008. Meer informatie: zie geregistreerde IB tekst. Volledige productinformatie is op aanvraag verkrijgbaar: Grünenthal B.V., B.V., Kosterijland Kosterijland 70-78, 70-78, 3981 3981 AJ AJBunnik, Bunnik. Tel: 030 60 735. 463 70. E-mail: [email protected] 030 – 24– 11 www.grunenthal.nl


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Verkorte productinformatie Bridion 100 mg/ml oplossing voor injectie Samenstelling: 1 ml Bridion 100mg/ml, oplossing voor injectie, bevat sugammadex als natriumzout equivalent aan 100 mg sugammadex. Elke ml bevat 9,7 mg natrium. Indicatie: Opheffing van de door rocuronium of vecuronium geïnduceerde neuromusculaire blokkade. Bij kinderen en adolescenten wordt het gebruik van sugammadex alleen aanbevolen bij standaardopheffing van een door rocuronium geïnduceerde neuromusculaire blokkade. Dosering: Sugammadex dient intraveneus te worden toegediend als eenmalige bolusinjectie. Sugammadex mag alleen worden toegediend door of onder supervisie van een anesthesist. Het gebruik van een geschikte neuromusculaire monitortechniek wordt aanbevolen om het herstel van de neuromusculaire blokkade te bewaken. De aanbevolen dosis sugammadex is afhankelijk van het niveau van de neuromusculaire blokkade. De aanbevolen dosis is niet afhankelijk van de toegediende anesthesie. Bridion kan worden verdund tot 10 mg/ml ten behoeve van een betere nauwkeurigheid van de dosering bij kinderen (zie rubriek 6.6*). Standaardopheffing: Er wordt een dosis van 4 mg/kg sugammadex aanbevolen indien het herstel ten minste 1–2 posttetanische tellingen (PTC) heeft bereikt na een door rocuronium of vecuronium geïnduceerde blokkade. Een dosis van 2 mg/kg sugammadex wordt aanbevolen als spontaan herstel is opgetreden tot minimaal het terugkeren van T2 na een door rocuronium of vecuronium geïnduceerde blokkade. Bij kinderen en adolescenten (2–17 jaar) wordt voor standaardopheffing bij terugkeer van T2 na een door rocuronium geïnduceerde blokkade 2 mg/ kg sugammadex aanbevolen. Andere situaties van standaardopheffing bij kinderen en adolescenten zijn niet onderzocht en worden daarom niet aanbevolen. Het gebruik van sugammadex bij voldragen pasgeborenen en zuigelingen wordt niet aanbevolen. Onmiddellijke opheffing: Als er klinische noodzaak bestaat van onmiddellijke opheffing na toediening van rocuronium, wordt een dosis van 16 mg/kg sugammadex aanbevolen. Onmiddellijke opheffing is bij kinderen en adolescenten niet onderzocht en wordt daarom niet aanbevolen. Hernieuwde toediening sugammadex: In de uitzonderlijke situatie dat zich postoperatief, na een initiële dosis van 2 mg/kg of 4 mg/kg, opnieuw een blokkade voordoet (zie rubriek 4.4*), wordt een herhalingsdosis van 4 mg/kg sugammadex aanbevolen. Contraindicaties: Overgevoeligheid voor het werkzame bestanddeel of voor één van de hulpstoffen. Waarschuwingen: Patiënten moeten kunstmatig worden beademd totdat de spontane ademhaling voldoende is hersteld. Andere geneesmiddelen, die tijdens en na de operatie zijn gebruikt, kunnen de ademhalingsfunctie onderdrukken. In geval dat hernieuwd optreden van een neuromusculaire blokkade wordt waargenomen, kunnen kunstmatige beademing en hernieuwde toediening van sugammadex noodzakelijk zijn (zie rubriek 4.2*). Om hernieuwd optreden van neuromusculaire blokkade te voorkomen, dienen de aanbevolen doses van sugammadex te worden gebruikt. Sugammadex mag niet worden gebruikt voor opheffing van blokkades geïnduceerd door niet steroïde neuromusculair blokkerende stoffen en door steroïde neuromusculair blokkerende stoffen, anders dan rocuronium of vecuronium. Indien de neuromusculaire blokkade wordt opgeheven onder voortzetting van de anesthesie, dienen aanvullende doses van het anestheticum en/of opioïd te worden gegeven op geleide van de klinische indicatie. Indien hernieuwde neuromusculaire blokkade is vereist vóór het verstrijken van de aanbevolen wachttijd van 24 uur, dient een nietsteroïde neuromusculair blokkerende stof te worden gebruikt. Sugammadex is niet onderzocht bij patiënten, die rocuronium of vecuronium krijgen op de Intensive Care. Mogelijke interacties: In situaties waar mogelijke verdringingsinteracties verwacht kunnen worden, dienen patiënten (na parenterale toediening van een ander geneesmiddel binnen 6 uur na toediening van sugammadex) zorgvuldig gecontroleerd te worden op tekenen van hernieuwd optreden van een blokkade (voor maximaal ongeveer 15 minuten). In situaties waar mogelijke bindingsinteracties kunnen optreden wordt de arts geadviseerd om het geneesmiddel opnieuw toe te dienen of de toediening van een therapeutisch gelijkwaardig geneesmiddel en/of niet farmacologische interventies te overwegen (zie rubriek 4.5*). Nierfunctiestoornis: Het gebruik van sugammadex bij patiënten met een ernstige nierfunctiestoornis wordt niet aanbevolen. Leverfunctiestoornis: Patiënten met een ernstige leverfunctiestoornis moeten met grote voorzichtigheid worden behandeld. Vertraagd herstel: Aandoeningen waarbij sprake is van een verlengde circulatietijd, zoals cardiovasculaire aandoeningen, gevorderde leeftijd of oedeemvorming kunnen gepaard gaan met langere hersteltijden. Allergische reacties: Artsen moeten voorbereid zijn op de mogelijkheid van allergische reacties en de nodige voorzorgsmaatregelen treffen. Natriumbeperkt dieet: Indien er meer dan 2,4 ml oplossing moet worden toegediend, dient hier rekening mee te worden gehouden bij patiënten met een natriumbeperkt dieet. Verlenging van het QTcinterval: De routinematige voorzorgsmaatregelen voor de behandeling van aritmie moeten in overweging worden genomen. Pediatrische populatie: De interacties en waarschuwingen voor volwassenen gelden ook voor kinderen. Interacties: Voor toremifeen, flucloxacilline en fusidinezuur konden verdringingsinteracties niet worden uitgesloten. Voor hormonale anticonceptiva kon een klinisch relevante bindingsinteractie niet worden uitgesloten. In het algemeen interfereert sugammadex niet met laboratoriumtests, met als mogelijke uitzondering de progesteronbepaling in serum en bepaalde stollingsparameters. Bijwerkingen: De veiligheid van sugammadex is beoordeeld op basis van een geïntegreerde veiligheidsdatabase van ongeveer 1700 patiënten en 120 vrijwilligers. Zeer vaak: Dysgeusie (metalen of bittere smaak), werd vooral waargenomen na doses van 32 mg/kg sugammadex of hoger. Vaak: Complicaties bij anesthesie, indicatief voor herstel van neuromusculaire functie. Soms: In een paar gevallen zijn allergieachtige reacties (bijv. bloedstuwing, erythemateuze huiduitslag) gerapporteerd na gebruik van sugammadex waarvan er een als milde allergische reactie is bevestigd. Na behandeling met sugammadex zijn enkele gevallen van awareness gerapporteerd. Hernieuwd optreden van een blokkade: De incidentie van het hernieuwd optreden van een blokkade was 2% na gebruik van sugammadex en 0% in de placebogroep. Vrijwel al deze gevallen kwamen voor in dose finding onderzoeken met suboptimale doses (minder dan 2 mg/kg) (zie rubriek 4.4*). Longpatiënten: Net als bij alle patiënten met een voorgeschiedenis van longcomplicaties, dient de arts zich bewust te zijn van het mogelijke optreden van bronchospasmen. Houder van de vergunning voor het in de handel brengen: N.V. Organon, Kloosterstraat 6, 5349 AB Oss, Nederland. Nummers van de vergunning voor het in de handel brengen: EU/1/08/466/001-2 Afleverstatus: U.R. Datum van eerste verlening van de vergunning: 25 juli 2008. *Voor de volledige productinformatie verwijzen wij naar de huidig goedgekeurde SPC.

bridion_vpi_9x13-04.indd 1

NovoSeven 1 mg (50 KIE), 2 mg (100 KIE), 5 mg (250 KIE), poeder en oplosmiddel voor oplossing voor injectie. (EU/1/96/006/004 EU/1/96/006/005 en EU/1/96/006/006). Samenstelling: Eptacog alfa (geactiveerd) 1 mg/injectieflacon, resp. 2 mg/injectieflacon, resp. 5 mg/injectieflacon (overeenkomend met 50, resp. 100, resp. 250 KIE per injectieflacon), recombinant stollingsfactor VIIa. Therapeutische indicatie: NovoSeven is geïndiceerd voor de behandeling van bloedingen en het voorkomen van bloedingen bij het ondergaan van operaties of invasieve ingrepen bij de volgende patiëntengroepen: bij patiënten met overgeërfde hemofilie die remmers tegen stollingsfactor VIII of IX hebben > 5 BU, bij patiënten met overgeërfde hemofilie bij wie een hoge anamnestische respons op factor VIII- of factor IX-toediening kan worden verwacht, bij patiënten met verworven hemofilie, bij patiënten met overgeërfde FVII-deficiëntie, bij patiënten met de ziekte van Glanzmann (trombasthenie) die antilichamen hebben tegen GP IIb-IIIa en/of HLA en bij wie in het verleden ongevoeligheid is opgetreden of bij wie overgevoeligheid bestaat voor bloedplaatjestransfusie. Contra-indicaties: Bekende overgevoeligheid voor het werkzame bestanddeel, de hulpstoffen of voor muis-, hamster- of rundereiwit kan een contra-indicatie zijn voor het gebruik van NovoSeven. Bijzondere waarschuwingen en voorzorgen bij gebruik: Onder pathologische omstandigheden waarbij weefselfactor in verhoogde mate kan worden aangetroffen, zou een verhoogd risico kunnen bestaan op het ontwikkelen van trombotische complicaties of het ontstaan van gedissemineerde intravasculaire stolling (DIS) in verband met de behandeling van NovoSeven. Deze omstandigheden kunnen ook gelden voor patiënten met gevorderde atherosclerose, crush syndroom, sepsis of DIS. In geval van ernstige bloedingen dient het product te worden toegediend in ziekenhuizen die bij voorkeur gespecialiseerd zijn in de behandeling van hemofiliepatiënten met remmers tegen stollingsfactor VIII of IX, of indien dat niet mogelijk is in nauwe samenwerking met een arts gespecialiseerd in de behandeling van hemofilie. De duur van de thuisbehandeling mag niet langer dan 24 uur zijn. Interacties met andere geneesmiddelen en andere vormen van interactie: Het risico van een mogelijke interactie van NovoSeven met stollingsfactorconcentraten is niet bekend. Gelijktijdig gebruik met protrombinecomplexconcentraten, geactiveerd of niet, moet worden vermeden. Antifibrinolytische middelen kunnen bloedverlies tijdens operatief ingrijpen bij hemofiliepatiënten beperken, met name bij orthopedische chirurgie en operaties in delen van het lichaam met veel fibrinolytische activiteit, zoals de mondholte. Ervaring met het gelijktijdig toedienen van antifibrinolytische therapie en rFVIIa is echter beperkt. Zwangerschap en borstvoeding: Het is niet bekend of NovoSeven, toegediend aan een zwangere vrouw, de foetus zou kunnen schaden, of de vruchtbaarheid zou kunnen beïnvloeden. NovoSeven dient uitsluitend te worden toegediend aan zwangere vrouwen indien dit noodzakelijk is. Het is niet bekend of NovoSeven wordt uitgescheiden in moedermelk. Men dient voorzichtig te zijn met het toedienen van NovoSeven bij vrouwen die borstvoeding geven. Bijwerkingen: Op basis van ervaringen na toelating op de geneesmiddelenmarkt komen ongewenste bijwerkingen zelden voor (< 1 per 1000 standaarddoses). Gedurende de post marketingperiode zijn de volgende ernstige bijwerkingen gerapporteerd: Arteriële trombotische complicaties zoals myocardinfarct of ischaemie, cerebrovasculaire aandoeningen en darminfarct, veneuze trombotische complicaties zoals tromboflebitis, diepe veneuze trombose en hieraan verwante pulmonale embolie. In de meerderheid van de gevallen waren de patiënten gepredisponeerd voor trombotische complicaties door gelijktijdige risicofactoren. Gedurende de post marketingperiode zijn geen spontane gevallen van anafylactische reacties gerapporteerd, maar patiënten met een verleden van allergische reacties dienen zorgvuldig te worden opgevolgd. Er zijn geen antilichamen tegen factor VII gerapporteerd bij patiënten met hemofilie A of B. Farmacotherapeutische categorie: Bloedstollingsfactoren, ATCcode: B02B D08 Afleverstatus: U.R. Vergoedingsstatus: Volledig vergoed. Datum: april 2008.

Anesthesia and Perioperative Care

4th Int. Erasmus Master Class Obese Patients

05-09-2008 11:40:41 2009 InterActie flyer v3.indd 1

EMCOP 2010 Organized by the Dept. of Anesthesiology Erasmus Medical Center Rotterdam

Friday 26 March and Saturday 27 March 2010 Congress Center De Doelen, Rotterdam, The Netherlands 10-02-2009 17:01:08

O nlin e tr i s o p a t io n en

r e g is

www.emcop.eu

21-04-09 17:02

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correspondence

Scientific misconduct in anesthesia research: no exception to the rule

1. Professor, Department of Anesthesiology, Leiden University Medical Center, 2300 RC LEIDEN, The Netherlands. 2. Conjoint Senior Lecturer, University of Sydney, Royal Prince Alfred Hospital, SYDNEY, Australia and editor of Anaesthesia and Intensive Care. 3. Professor, Columbia University, NEW YORK, NY 10032, USA and Editor-in-Chief Anesthesia & Analgesia.

J.W. van Kleef, MD PhD1 J. Loadsman, MB, BS, PhD, FANZCA2 S. Shafer, MD3 A. Dahan, MD PhD1

Introduction Biomedical research is a fundamental and intrinsic part of modern society. For our specialty –anesthesiology and pain treatment– the intention of research is to understand physiology and pharmacology, and to study the impact of disease on physiology and pharmacology in its broadest sense; our research should improve patient care and treatment, reduce/ prevent suffering, and fight/prevent disease. Medical research requires the participation of patients or healthy volunteers as subjects in possibly harmful or at least stressful experiments. The relationship between patient or volunteers and doctor or researcher is complex and sometimes unclear, and taking into account the history of malicious research, society has developed a set of managerial and ethical guidelines for the conduct of medical research. The academic world has accepted these guidelines, which in fact are an extension to the generally applicable legal codes. In the Netherlands, departmental and institutional science committees, the local institutional ethics committee (IEC), the Central Committee on Research involving Human Subjects (de Central Commissie Mensgebonden Onderzoek (CCMO)), and the boards of the institution where the research is conducted are responsible for the guidance and review of medical


research; a process which starts at the submission of the research protocol and continues indefinitely, even after the data have been published. Humans are humans, however, and there is always a minority among us who, for whatever reasons, bend or even break the rules. In this short review we will discuss some examples of scientific misconduct in general and in particular some recent examples of misconduct within our own field.

What is research? First we need to define what research is. We define research as the gathering data to create generalizable knowledge. A good rule of thumb is that if you intend to publish what you find, it is research. All human research requires approval from an ethics committee. Furthermore, all prospective human research requires informed consent from the subjects involved or their legal guardians. In some circumstances, retrospective research can be done with a waiver of consent but the advice of the IEC should be sought. The National Health and Medical Research Council of Australia has published a document (http://www.nhmrc.gov. au/publications/synopses/e46syn. htm) giving advice to researchers, IECs and journal editors regarding the collection and publication of audit data.

What is misconduct? Next, we need to define what we consider scientific misconduct. The US based Office of Research Integrity defines research misconduct as follows (see http://ori.dhhs.gov/ ® misconduct ® definition of research misconduct): Research misconduct means fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results, where: a. fabrication is making up data or results and recording or reporting them; b. falsification is manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately presented in the research record; c. plagiarism is the appropriation of another person’s ideas, processes, results, or words without giving appropriate credit; We would like to add that research misconduct includes performing research in the absence of ethics approval (this includes the absence of a written and structured protocol identifying the proposed study methods and analysis techniques); and self plagiarism (i.e., replication of earlier statements without appropriate referral) and duplicate publication/ submission. Note that research misconduct does not include honest error or differences of opinion.

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Large scale data manipulation and fabrication Scientific misconduct has been discovered in all fields of science, from archeology to zoology. Few such episodes, however, have been widely reported to the general public. Often this is because of the degree of misconduct or the particular topic. Journals such as Nature and Science regularly publish on this issue and less influential journals also present occasional misconduct cases. There is the steady stream of retractions as a sign of serious misconduct but these likely represent the tip of the iceberg. One of the first cases of scientific fraud in medicine that received ample attention because of its extraordinary scale was that of Dr. John Darsee [1, 2]. In the 1980’s it was discovered that Darsee fabricated much of the data that was published in over 100 publications on cardiac research. A number of factors make this case intriguing. Darsee had 47 co-authors from two major US medical schools. Some of the misconduct was obvious, for example, in one paper he presented the pedigree of a family with a high incidence of a rare cardiac disease and the pedigree included a 17 year old father that supposedly impregnated the mother of his first child at the age of 8 or 9, and his second child at age 9 or 10, yet neither the co-authors nor the reviewers of the paper took notice of this. It also took a very long time before all the misconduct was discovered and even when part of the fraud was acknowledged Darsee remained at the Cardiac Research Laboratory performing his research. More recently, the Norwegian dentist Jon Sudbø confessed to creating 900 fictitious patients in a 2005 Lancet paper showing that non-COX2 NSAIDs reduce the risk of oral cancer in smokers (250 of these patients had the same date of birth!) [3]. Later, it was also found that in 15 of 38 other publications (including a publication in the New England Journal of Medicine and his dissertation) data were fabricated or manipulated.


Hwang Woo-Suk, a professor of biotechnology at Seoul National University (South Korea) published two stunning and break-through papers in Science on stem cell research. He reported the production of human embryonic stem cells from cloned human embryos [3]. Immediately after the publications there were several allegations of fraud, leading to a fourweek investigation by the University and the announcement that all of the claims made in the papers were fabricated. Outside biomedicine there were fraud cases that received attention by the lay press. One example is that of Jan Hendrik Schön [3]. Schön was considered a hard working, brilliant and productive physicist with a bright future. He reported in Nature that using a thin layer of organic dye molecules he was able to construct a transistor. Evidently, this was a magnificent discovery, as it would open the possibility for organic rather than silicon based electronics. It would have reduced the size of the computer chip beyond the current possibilities and allow the extension of Moore’s law for much longer than anticipated. However, his star fell rapidly to earth when it was discovered that he had falsified data in at least 16 papers in Nature and Science. In an investigational report it was concluded that Schön “showed reckless disregard for the sanctity of data in the value system of science.” These four cases presented above were chosen because they exemplify the complexity, ingenuity and maliciousness but also the naiveté of those who perform scientific misconduct. The scale of misconduct and level of publication is exceptional. Most cases of misconduct are performed on a much smaller scale and involve publications in less prestigious journals than Nature, Science and The New England Journal of Medicine. But still these less publicized cases equally deserve our attention as they may influence our professional behavior and consequently may harm our patients. This leads to the question

of ‘how much fraud is there?’ and this is hard to answer. Reports on misconduct are often shrouded in confidentiality, justified or otherwise. For some figures, see the website of the Office of Research Integrity and reference 3.

Misconduct in anesthesia research The number of misconduct cases reported within our own field is limited. This may suggest that only a few cases exist or, more probably, it simply indicates that we have not unearthed the majority of cases.

Misrepresentation of study design The first two examples that we review here both involve the description of a study as ‘prospective randomized’ while in fact they were not. This may be driven by fear of rejection since observational studies carry much less weight than randomized studies and will have a higher chance of not meeting the reviewer’s or editor’s criteria for acceptance. False portrayal of a study as randomized and prospective may convince colleagues to adopt the treatments they now consider effective and superior to other therapies while in reality they are not. The first example is a study published in 2005 in Regional Anesthesia and Pain Medicine [4]. The study, on the use of acupuncture points versus conventional landmarks to localize the femoral nerve when planning a femoral nerve block, initially involved two study groups. When in a first submission to another journal the paper was rejected the authors added a third group (as suggested by one of the reviewers) and subsequently, in their next submission (now to Regional Anesthesia and Pain Medicine), presented the allocation of patients to one of the three groups as random. The paper was accepted. Fortuitously, one of the reviewers involved in the submission to the first journal discovered the misrepresentation of the design and contacted the latter journal. The paper was retracted in 2006 [5].

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The second example is from our own ranks (LUMC) and involved a publication in the Journal of Thoracic and Cardiovascular Surgery in 2005 on the use of dexamethasone in pediatric cardiac surgery to reduce gut permeability [6]. Again the study was presented as prospective and randomized while it was observational. A letter from the Central Committee on Research involving Human Subjects (CCMO) resulted in contact with the editor of the journal. Interestingly, he allowed a second round of independent review. Now it was concluded that the study was underpowered to draw any conclusions with adequate certainty and the reviewers and editor rejected the paper for publication as an observational study and subsequently the paper was retracted [7]. The role of the co-authors in these examples remains undefined (as is often true for papers involving misconduct). Co-authors are required to know the protocol, participate in the performance of the study and/or in the analysis of the collected data and/ or in the writing of the paper. They all must have read the final version of the paper and agree with its content. Whether or not this was the case in these two examples is unknown but irrespective, all co-authors carry as much blame as the main/first author of the retracted papers. Discovery of a case of incorrect description of the study design or data manipulation is difficult. The discovery of the misconduct in these two cases seems unusual. This is particularly true in the first case. However, the fact that the CCMO tracks reports of studies involving minors is not at all surprising as the CCMO carries a restricted policy on randomized blinded studies in children (no, unless …..) and apparently carefully safeguards the process. Another recent example of misrepresentation of data involves two in vitro studies by Mandal et al. purportedly demonstrating an effect of inhalational anesthetics on the oligomerisation of amyloid


precursors, the oligomers being associated with the development of Alzheimer’s disease [8, 9]. Both papers were later retracted (one retraction was published as an erratum) [10, 11]. According to the retraction notices, the actual anesthetic concentrations used in the experiments were 8-10 times higher than that reported in the paper (already well above the clinically relevant range). Unfortunately, the publication of Mandal’s results had already been widely reported in the lay media after institutional press releases. The popular science journal New Scientist [12] quoted Mandal thus: “It is a seriously deadly combination when an older person receives halothane.” While a number of specialists in this field immediately responded to this with a letter referring to Mandal’s statement as “grossly premature” and “bordering on irresponsibility”, and stating that “there are no adequate animal or clinical studies to support it,” [13] the public damage had already been done. It is also notable that, according to the retractions, the main author had published at least one of the papers without giving the co-authors the opportunity to review the submitted manuscript [10].

Plagiarism, self-plagiarism and duplicate publications Self-plagiarism or the use of your own previously published material without attribution may be acceptable in some settings but problematic in others. We, for example, accept similar descriptions of a specific methodology in various papers from the same group. Duplication of material from abstracts of conference proceedings in a subsequent journal publication is considered acceptable by most journals. Not acceptable is a duplicate publication without attribution in two distinct scientific journals. One recent example we know about is: The legend of the P value, published in 2005 in Anesthesia & Analgesia,[14] and P less than .05: what does it really mean? published in Pediatrics in 2007 [15]. When the duplication was discovered, the authors volunteered to retract the Pediatrics paper [16].

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Plagiarism or the use of previously published material without attribution probably occurs frequently and is often the result of non-English speaking authors grabbing verbatim text from another paper. There are even examples of the copying of a complete paper in which only the authors differ. In an apparent example, Andre de Wolff and colleagues published a paper in Anesthesiology in 1993 entitled “Insulin decreases the serum potassium concentration during anhepatic stage of liver transplantation” [17]. In 2004 an almost verbatim copy of the paper appeared in the World Journal of Gastroenterology by Li et al. [18]. The title was now “Effect of insulin on hyperkalemia during anhepatic stage of liver transplantation”. From the same group of authors another paper entitled “Isoflurane preserves energy balance in isolated hepatocytes during in vitro anoxia/reoxygenation” was published in 2005 in the World Journal of Gastroenterology [19]. It too appears to be, more or less, a verbatim copy of the work of Samuta and colleagues (Effects of isoflurane dose, duration of anoxia, and reoxygenation on isoflurane’s preservation of energy balance in anoxic isolated hepatocytes), published in 1993 in Anesthesia & Analgesia [20]. At present it remains unknown what action is to be taken in these cases. There is a publicly available website that attempts to identify duplicate biomedical publications. It is entitled Deja Vu: a Database of Highly Similar and Duplicate Citations. The database uses text matching software (eTBLAST) and scans related abstracts in PubMed looking for evidence of duplicate publication. It generates a similarity score for potential duplicates using heuristic algorithms and also notes papers that have already been identified as duplicate submissions, some of which have been retracted. The web address is http://discovery. swmed.edu/dejavu/. See also [21].

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opinion Other forms of unethical behavior One important form of misconduct is the performance of research without protocol and/or ethics approval. Often it is thought that data collection per se or without the need for randomization or blinding does not require IEC approval. This is not correct. As stated earlier, all forms of data collection done with the intention to publish are considered research and the IEC should always be consulted regarding the need for approval and patient consent. As an editor-in-chief of Anesthesia & Analgesia one of us (Steve Shafer) frequently receives submissions in which either IEC approval or informed consent (or both) were neglected. One example is a study in which supralaryngeal airways were tested in obese patients without IEC approval. Finally, there are cases in which scientists make inappropriate use of specific tools in their research. One example is the use of genetically modified material without consent of the manufacturer/ engineer. Recently, Luo et al. [22]

published a paper in Anesthesia & Analgesia in which they reported the use of mutant HERG channels expressed in human embryonic kidney cells. The Canadian scientist Zheng (not involved in the mentioned publication) contacted the Editorin-Chief and explained that he had developed the HERG mutants described in the paper. He further stated that the first author had been a post-doctoral researcher for six months in Zheng’s laboratory, and that he lacked the technical expertise to produce the mutants. Zheng wanted to know where Luo had obtained his material. Confronted, the authors acknowledged that the HERG mutants were from Zheng’s laboratory and were used without consent. They requested the retraction of their paper [23].

Concluding remarks We have noted a set of examples of scientific misconduct discovered during the process of submission, peer review or after publication. Many occurrences of misconduct

remain unidentified and there is evidence that it is common, one study finding that one in six papers contained some form of redundancy or plagiarism [24]. The question ‘why do people do what they do?’ is hard to answer when considering scientific misconduct. Outright malicious intent is not always the driving force. Inexperience, naiveté and the lack of good mentorship and guidance as well as the absence of training in the ethics of scientific research are often partly responsible. Clearly, individual cases of scientific misconduct are always open to debate. Irrespective of cause or intent, when scientific misconduct is perpetrated there are many losers: the scientific community, the journals and, most importantly, the general public who continue to trust physicians and researchers and support them. Whether or not the misconduct is subsequently discovered, the authors have lost their integrity. Should it be discovered however, and this is becoming increasingly likely, they stand to lose a great deal more.

references 1. Ross R.S. Report of an ad hoc advisory committee to the dean of the Harvard Medical School on dishonesty in scientific research. Harvard University Gazett 1982; 77: 11-2. 2. http://en.wikipedia.org/wiki/John_ Darsee (July 5, 2007). 3. Odling-Smee L., Giles J., Fuyuno I., Cyranoski D., Marris M. Where are they now? Nature 2007; 445: 244-5. 4. Schulz-Stübner S., Henszel A., Hata J.S. A new rule for femoral nerve blocks. Reg Anesth Pain Med 2005; 30: 473-7. 5. Notification of retraction [of SchulzStübner et al. Reg Anesth Pain Med 2005; 30: 473-477]. Reg Anesth Pain Med 2006; 31: 385. 6. Malagon I., Onkenhout W., Klok M., Linthorst L., van der Poel P.F.H., Bovill J.G., Hazekamp M.G. Dexamethasone reduces gut permeability in pediatric cardiac surgery. J Thor Cardiovasc Surg 2005; 130: 265-71. 7. Notice of retraction [of Malagon et al. J Thor Cardiovasc Surg 2005; 130: 265-271]. J Thor Cardiovasc Surg 2007; 134: 771. 8. Mandal P.K., Pettegrew J.W., McKeag D.W., Mandal R. Alzheimer’s disease: halothane induces Aß peptide to oligomeric form-solution NMR studies. Neurochem Res 2006;31:883–90.


9. Mandal P.K., Williams J.P., Mandal R. Molecular understanding of Aß peptide interaction with isoflurane, propofol, and thiopental: NMR spectroscopic study. Biochemistry 2007;46:762-71. 10. Mandal P.K., Pettegrew J.W., McKeag D.W., Mandal R. Erratum [to Mandal et al. Neurochem Res (2006) 31:883–90]. Neurochem Res 2008;33:220. 11. Mandal P.K., Williams J.P., Mandal R. Correction to Biochemistry 2007;46:762-71. Biochemistry 2007;46:12887. 12. Philips H. Alzheimer’s alert over anaesthetics. New Scientist 2006;2575:12. 13. Crosby G., Culley D., Xie Z., Eckenhoff R. Fear of anaesthesia. New Scientist 2007;2594:22. 14. Kain Z.N. The legend of the P value. Anesth Analg 2005; 101:1454-6. 15. Kain Z.N., MacLaren J. P less than .05: what does it really mean? Pediatrics 2007;120:698. 16. Kain Z.N., MacLaren J. P less than .05: what does it really mean? [retraction of Kain Z.N., MacLaren J. Pediatrics. 2007; 119:608-610]. Pediatrics 2007; 120:698. 17. de Wolff A., Frenette L., Kang Y., Tang C. Insulin decreases the serum potassium concentration during the anhepatic stage of liver transplantation. Anesthesiology 1993; 78: 677-82.

18. Li Q., Zhou M.-T., Wang Y., Liu Y.-H., Yang L.-Q., Zhu M., Yu W.-F., Yang G.-S. Effect of insulin on hyperkalemia during anhepatic stage of liver transplantation. World J Gastroenterol 2004; 10: 2427-9. 19. Li Q., Yu W.F., Zhou M.T., Lu X., Yang L.Q., Zhu M. Isoflurane preserves energy balance in isolated hepatocytes during in vitro anoxia/ reoxygenation. World J Gastroenterol 2005; 11:3920-4. 20. Samuta T., Becker G.L., Pohorecki R., Armstrong K., Landers D.F. Effects of isoflurane dose, duration of anoxia, and reoxygenation on isoflurane’s preservation of energy balance in anoxic isolated hepatocytes. Anesth Analg 1993; 77:38-43. 21. Errami M., Garner H. A tale of two citations. Nature 2008; 451: 397-9. 22. Luo T., Luo A., Liu M., Liu X. Inhibition of the HERG Channel by Droperidol Depends on Channel Gating and Involves the S6 Residue F656. Anesth Analg 2008;106:116170. 23. Notice of retraction [of Luo et al. Anesth Analg 2008;106:1161-1170]. Anesth Analg 2008;107:1040. 24. Schein M., Paladugu R. Redundant surgical publications: Tip of the iceberg? Surgery 2001;129:655-61.

further readin g Sox H.C., Rennie D. Research misconduct, retraction and cleansing the medical literature: lessons from the Poehlman case. Ann Int Med 2006;144:609-613. Drummond G., Loadsman J. Medical fraud: more than high profile misconduct. European Society of Anaesthesiology Newsletter 2006;29:5-6. Roberts I., Smith R., Evans S. Doubts over head injury studies. BMJ 2007; 334: 392-394. Loadsman J.A., Garner H.R., Drummond G.B. Towards the elimination of duplication in Anaesthesia and Intensive Care (editorial). Anaesth Intensive Care 2008;36:643-645. The 2008 Anesthesia & Analgesia Guide for Author. Anesth Analg 2008; 107:250-263.

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Sugammadex (Bridion®) in de praktijk bij Rolf Brouwer, Spaarne Ziekenhuis te Hoofddorp:

“Veiligheid, flexibiliteit én vlotte doorstroming in de OK”

Spierverslapping door middelen als rocuronium (Esmeron® ) en vecuronium (Norcuron® ) is een belangrijk instrument om operatieomstandig heden te verbeteren en intubatie en kunst matige ademhaling mogelijk te maken. Het opheffen van verslapping, nodig om patiënten hun normale spierfuncties terug te geven en sneller weer zelf standig te laten ademhalen, is een verhaal apart. De huidige opheffings middelen hebben behalve een trage werking soms ook ongewenste bij werkingen, zoals hartritmestoornissen, maagdarmklachten en problemen met de luchtwegen1,2,3. Daarnaast is nadruk kelijke monitoring vereist door de ane sthesioloog, waarbij de duur per patiënt en per situatie flink kan verschillen. Anesthesist Rolf Brouwer en zijn collega’s in het Spaarne Ziekenhuis hebben in de afgelopen zes maanden de voordelen van sugammadex als eerste geregistreerd en enige selectieve relaxant binding agent (SRBA) leren kennen. “Ik durf het gerust een pareltje in ons farmacainstrumentarium te noemen. Een blijvertje inmiddels ook, die we met name bij buikoperaties, kaakoperaties en bij KNOingrepen in de dag behandeling veelvuldig inzetten.” Het product wordt in Hoofddorp gericht toegepast bij operaties waarbij de patiënt moet worden geïntubeerd. “Als er verslapt moet worden, kies ik voor opheffing met sugammadex en in die beslissing speelt veiligheid een grote rol. Uiteraard zijn we scherp op de parameters die bepalen of een patiënt veilig naar de uitslaapkamer of naar de afdeling kan. In de beoordeling van de scores van de patiënt op die parameters zit een veiligheids marge, die enig beoordelingsvermogen vergt. Als ik sugammadex toepas, is de verslapping binnen minuten opgeheven en heb ik sneller duidelijkheid dat de patiënt veilig weg kan. Zo kan ik mijn aandacht met een gerust hart op een volgende patiënt richten.” De snelle werking heeft ook voordelen bij het managen van drukke OKschema. “Tot dusver moesten we maar afwachten hoe snel het precies kon gaan, met alle nare gevolgen voor de OKplanning. Nu kan de patiënt bijna altijd binnen minuten worden gedetubeerd en daarna op eigen kracht van de operatietafel stappen.”

Dat betekent nog al wat voor de ‘business case’ van een ziekenhuis dat op drukke dagen in de dagbehandeling tot 18 patiënten per OK wil opereren. “Op zo’n dag, waarop wij de dagbehandelingsbedden dubbel bezet hebben, moeten wij hier een soepel lopende organisatie hebben, met zo min mogelijk onzekerheden. Met sugammadex hebben wij de prettige zekerheid van een snelle en veilige doorstroming met alle bijkomende capaciteits en kostenvoordelen van dien.” Ook biedt sugammadex in Brouwer’s ervaring extra armslag bij het oplossen van complicaties. “Toen zich onlangs problemen voordeden bij de extubatie van een patiënt, heb ik het product snel toegepast. Daarmee kan ik bij de probleemanalyse de mogelijkheid van restspierverslapping al vast wegstrepen. Dat leverde kostbare tijdwinst op, die in het voordeel van de patiënt heeft gewerkt.” Brouwer heeft sugammadex altijd binnen handbereik voor deze situaties en voor een ‘Cannot Intubate, Cannot Ventilate’ situatie bij het gebruik van een langwerkend spierverslappend middel. “Daar is het een noodgereed schap bij uitstek om de ademweg vrij te krijgen.” Verder heeft de anesthesist nu meer moge lijkheden in het samenspel met de chirurg. Wil de chirurg dat de patiënt in de eindfase van de operatie goed is verslapt, dan kan de anesthesist hierin zonder meer voorzien, want sugammadex kan de verslapping in korte tijd weer teniet doen. Kosten wegen zwaar tegenwoordig, dat beseft ook Brouwer. “Maar in het geheel van alle operatiekosten is het een relatief kleine kostencomponent. Kosten die, vind ik, ruimschoots worden gecompenseerd door baten in veiligheid, flexibiliteit en efficiency. Als je met je maatschap een rol van betekenis wilt spelen in het ziekenhuis, dan moet je je sterk maken voor bepaalde procedures en middelen om veilig maar ook efficiënt te kunnen werken. Dit middel gaat een belangrijke rol spelen in het management van OK’s in dagbehandelingcentra.” Verkorte productinformatie zie elders in dit blad.

Referenties: 1.

2.

3.

O.Sacan et al. Sugammadex reversal of rocuroniuminduced neuromuscular blockade: a comparison with neostigmineglycopyrrolate and edrophonium atropine. Anesth Analg, vol. 104, No.3 March 2007 E.A.Flockton et al. Reversal of rocuroniuminduced neuromuscular block with sugammadex is faster than reversal of cisatracuriuminduced block with neostigmine. British J of Anesth. 2008; 100: 62230 James E. Caldwell,. Reversal of Residual Neuromuscular Block with Neostigmine at One to Four Hours after a Single Intubating Dose of Vecuronium An&h Analg 1995;80:116874

2009NL295

Met de introductie van sugammadex (Bridion®) heeft de ane sthesist een nieuw instrument in handen om spierverslapping snel op te heffen. Dat werkzaamheid binnen minuten cruciaal kan zijn bij kritieke situaties, is voor anesthesiolooog Rolf Brouwer in het Spaarne Ziekenhuis in Hoofddorp een belang rijke reden om het product in de OKapotheek op te nemen. Maar de echte eyeopener van sugammadex bleek in het Spaarne Ziekenhuis van bedrijfseconomische aard te zijn. “Met sugammadex elimineren we onzekerheden, die een OK schema tot dusver in de war konden sturen.”

Dit interview is mogelijk gemaakt door ScheringPlough Nederland

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Young Investigators Grant 2007

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1 Leids Universitair Medisch Centrum Afdeling Anesthesiologie

Opioïd-geïnduceerde hyperalgesie ontstaat onafhankelijk van opioïdreceptor-activatie E.Y. Sarton, MD PhD1

‘In 2007 ontving ik de Young Investigators Grant (YIG) van onze vereniging. Het project dat ik toen gestart ben behelst het quantificeren en modeleren van opioïdeffect in het brein. Als eerste stap heb ik gekozen om het paradoxale effect van opioïden, de zogenaamde opioïd-geïnduceerde hyperalgesie (OIH), te bestuderen in een translationele aanpak door het meten van OIH in muis en mens. De studie groeide uit tot een project op zich en heeft geresulteerd in een recente publicatie in Anesthesiology (juni 2009: Morphine6b-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans) met bijbehorend editorial van de hand van de klinisch-farmacoloog Jörn Lötsch [1, 2]. In dit verslag geef ik een korte samenvatting van het artikel. Het onderzoek wordt door mij voortgezet en het ligt in de bedoeling de intracerebrale locatie van OIH inclusief de moleculaire mechanismen verder te onderzoeken.’ Elise Sarton

Inleiding Opioïden hebben een aantal belangrijke bijwerkingen, waaronder de paradoxale toename in pijngevoeligheid, de zogenaamde opioïd-geïnduceerde hyperalgesie (OIH). OIH leidt tot een toename in dosering en bemoeilijkt de behandeling van chronische pijn patiënten. Echter OIH komt ook voor na de acute toediening van opioïden en vermindert de analgetische werking met als gevolg de noodzaak van het toedienen van relatief hoge doseringen of oplopende doseringen. Huidige theorieën


die het fenomeen OIH pogen te verklaren gaan uit van de activatie van de m- opioïdreceptor en/of het optreden van analgesie als belangrijke etiologisch moment(en). Bijvoorbeeld, de activatie van zogenaamde excitatoire m-opioïdreceptoren (Gsgekoppelde m-opioïdreceptoren) in het DRG (dorsal root ganglion) kan aanleiding zijn tot OIH. Andere theorieën gaan uit van hyperalgesie als een inherente automatische consequentie c.q. aanpassing van/aan opioïdanalgesie. In de huidige studie onderzoeken wij onder leiding van Prof.

Albert Dahan en in samenwerking met een groep neurowetenschappers in New York onder leiding van Prof. Banjamin Kest of het mogelijk is OIH te induceren zonder activatie van de opioïdreceptor. Tevens onderzoeken we de rol van de NMDA receptor in het ontstaan van de OIH.

Methodiek en Resultaten Experimenten zijn uitgevoerd in mens en dier na toestemming van de lokale Commissie Medische Ethiek en Dier Ethische Commissie.

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Figuur 1. A. Effect van 10 mg/kg sc M6G in de CD1 muis. Het effect van totale opioïdreceptor blokkade met naltrexone is zichtbaar als de snelle ontwikkeling van hyperalgesie (i.e., afname van de staart ‘twitch’ tijd). De controle muis toont slechts analgesie. B. Effect van 10 mg/kg sc M6G in de TKO muis (hyperalgesie) en in de muis met intacte opioïdreceptoren (potente analgesie).

STUDIE 1 Het analgetisch effect van acute toediening van morfine-6-glucuronide (M6G) in de muis met intacte opioïdreceptoren (CD-1 muis) tijdens blootstelling aan hoge doses naltrexon en muizen zonder functionele m-, k- en d-opioïdreceptoren (zogenaamde Triple Knockout Mice of TKO). Antinociceptie wordt gemeten met behulp van de ‘tail-withdrawal-test’ (TWT) waarin de staart van de muis in warm water wordt gedoopt (gemiddelde temperatuur 47.3o C) en de tijd tot terugtrekking (in seconden) wordt gemeten (staart ‘twitch’). Om de staart niet te beschadigen wordt een limiet van 30 s aangehouden. Het effect van 10 mg/kg sc M6G in de CD-1 muis is potente en langdurige analgesie en wordt de limiet van 30 s in de TWT al na 30 minuten bereikt; in de TKO muis echter ontstaat geen analgesie maar ontwikkelt de muis hyperalgesie in de TWT (staart ‘twitch’ tijd reduceert van 10.5 tot < 8 s). Eenzelfde antwoord wordt gezien


na de toediening van M6G in de CD-1 muis tijdens de blootstelling aan naltrexon. Zie ook figuur 1.

STUDIE 2 Het analgetica effect van chronische toediening van M6G in de CD1 muis tijdens de toediening van naltrexon of placebo. M6G en naltrexon/placebo worden toegediend via osmotische pompjes die operatief zijn ingebracht in de muis. Onder beide omstandigheden (placebo en naltrexon) ontwikkelt de muis hyperalgesie binnen 24 uur. Het hyperalgetisch effect (afname van de staart ‘twitch’ tijd van 9 tot 5-6 s) houdt minimaal 6 dagen aan.

STUDIE 3 Het effect van NMDA receptor antagonisme op M6G hyperalgesie in het acute en chronische experiment. MK801, een effectieve en langwerkende NMDA receptorantagonist, heeft een preventief effect in het acute M6G experiment (hyperalgesie treedt niet op) en heft de hyperalgesie in het

chronisch experiment binnen 30 minuten volledig op.

STUDIE 4 Studie 4 is een dubbelblinde gerandomiseerde studie in gezonde vrijwilligers (n = 40). 0.4 mg/kg M6G of placebo (NaCl 0.9%) iv wordt toegediend tijdens een achtergrond iv infusie van naloxon of placebo en het antwoord op experimentele hittepijn (TSA II, Medoc, Israël) wordt gemeten met behulp van een limerickje meting (NRS). In tegenstelling tot placebo dat geen effect heeft, ontwikkelen alle proefpersonen een sterk hyperalgetische reactie na toediening van M6G. Dit effect is onafhankelijk van de achtergrondinfusie.

Conclusies en discussie Samenvattend, M6G hyperalgesie treedt op in muis en mens onafhankelijk van de activatie van de opioidreceptor; in de muis zijn er aanwijzingen voor betrokkenheid van de NMDA receptor bij OIH.

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De afwezigheid van de noodzaak van opioïdreceptoractivatie bij het ontstaan van OIH en de snelle ontwikkeling van OIH na toediening van M6G zijn belangrijke bevindingen. M6G is de actieve metaboliet van morfine. Tot voor kort werd aangenomen dat OIH na morfine geheel en al toe te schrijven is aan de belangrijkste morfinemetaboliet, M3G. Deze studie laat duidelijk zien dat in muis en mens de andere morfineglucuronide tot het zelfde in staat is, mogelijk via activatie van de NMDA receptor. Andere studies in de muis (waaronder nog niet gepubliceerde data) laten zien dat ook fentanyl, morfine en oxymorphone OIH veroorzaken zonder dat er sprake is van activatie van de opioïdreceptor. In tegenstelling tot de muis treedt geen snelle hyperalgesie op na toediening van morfine of fentanyl in de mens, althans niet zichtbaar. Mogelijk wordt de hyperalgesie overschaduwd door het sterke analgetisch effect dat deze stoffen hebben (in

tegenstelling tot M6G dat slechts een matige potentie heeft in de mens). Het is duidelijk dat het gemeten analgetisch effect een optelsom is van analgesie veroorzaakt door activatie van de mopioïdreceptor PLUS hyperalgesie door non-opioïdreceptoractivatie. De mechanistische rol die de NMDA receptor in dit geheel speelt blijft nog onduidelijk. Wel wordt duidelijk dat NMDA receptor blokkade door het wegnemen van de OIH opioïdanalgesie kan verbeteren en de kans op tolerantie kan verminderen. Klinische studies hebben dit effect via toediening van ketamine al eerder aangetoond.

Dankwoord Ten slotte, wil ik de Nederlandse Vereniging voor Anesthesiologie graag danken voor de toediening van de YIG 2007. Toekenning van deze beurs heeft geleid tot innovatief translationeel onderzoek. Jim Eisenach (de hoofdre-

dacteur van Anesthesiology) schrijft na een eerste beoordeling van het oorspronkelijke manuscript: “We all agree that this work is interesting, addressing a long standing controversy, is reasonably definitive, and is very translational. Exactly what we’re looking for at Anesthesiology!” Een boodschap die we allen ter harte kunnen nemen.

referenties 1. van Dorp E.L.A., Kest B., Kowalczyk W.J., Morariu A.M., Waxman A.R., Arout C.A., Dahan A., Sarton E.Y. Morphine-6b-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology. 110:1356-1363, June 2009. 2. Lötsch J. Pleiotropic Effects of morphine-6bglucuronide. Anesthesiology. 110:1209-1210, June 2009.

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